PATENT APPLICATIONS

VII. PATENT APPLICATIONS

A. Provisional Application Since 1995, a provisional patent application may be filed with the USPTO

for the purpose of establishing priority of invention and the benefit of an earlier filing date but not starting the 20-year patent term. A patent does not issue from filing a provisional application, and the application automatically becomes abandoned after 1 year from filing. To obtain the benefit of an earlier filing date, a regular or nonprovisional patent application must be filed before the end of the 1-year period. The provisional application need only contain a written description of the invention, drawings (if needed) and the name of the inventor(s) along with some formal requirements and a fee.

Patent Considerations 705 No claims are required in the application, but the invention must be fully

disclosed to support the claims of a subsequent regular application, other- wise the benefit of the earlier filing date would only apply to the claims supported by the disclosure in the provisional application.

B. Nonprovisional Application

A regular application submitted to the USPTO to obtain a patent consists of

a number of parts prepared by a patent legal specialist with the aid of the inventor(s). The following sections will focus on two major parts of the application that are incorporated into the issued patent. These parts are the patent specification and the claims.

VIII. PATENT SPECIFICATION The specification is the written description of the invention that concludes

with one or more claims that define the exclusive rights granted to the inventor. The specification is usually presented in several subparts:

1. Title of the Invention . A short and specific description of the nature of the invention.

2. Cross-Reference to Related Applications, if any . These are prior filed applications of the same applicant and, if certain require- ments are met, establish the earliest effective filing date for some or all of the claimed subject matter. Several types that may appear in the patent are:

a. Continuation—for the same invention but may be used to add claims to subject matter disclosed but not claimed in the ear- lier application.

b. Continuation-in-part—contains some or all of the prior appli- cation plus new information disclosed (new matter) to sup- port new claims.

c. Divisional—filed for distinct or independent inventions than cannot be claimed in the same application.

d. Provisional—previously discussed. For benefit of earlier filing date.

e. Foreign or international application—Establish priority (ear- lier) filing date.

3. Background of the Invention . Consists of two parts—a brief state- ment of the field of art to which subject matter pertains, and a

706 Roehrs description of the relevant prior art including problems, limita-

tions, disadvantages in the prior art and those that have been solved or overcome by the applicant’s invention.

4. Summary of the Invention . A brief summary that presents the substance or general idea of the invention and may include the objective’s of the invention and may point out advantages and how it solves problems presented in the Background.

5. Brief Description of the Drawings . Drawings are not always required unless they are needed for a full understanding of the claimed subject matter. Drawings are more commonly used in mechanical and electrical patents. However, graphical presenta- tions of experimental data are also considered drawings and sometimes are used in composition of matter patents.

6. Detailed Description . This section presents the invention described in sufficient detail to support the scope of the claimed subject matter and distinguish it from other inventions and what is old (prior art). It is also used to meet the patent law require- ments to describe the method of making and using it in sufficient detail to allow a person skilled in the art to make and use the invention without undue experimentation, and the best mode (preferred embodiment) contemplated by the inventor for practi- cing the invention at the time of filing the application. If there are drawings, each element should be described. For improvement inventions, it points out specifically the part or parts of the stat- utory subject matter such as a composition of matter that is the improvement. It is understood in patent law that the inventor is his own lexicographer and has latitude in choosing the terminol- ogy to describe and claim his invention, but there must be corre- spondence in terminology between the description, claims, and drawings.

7. Abstract of the Invention . A brief statement of the technical dis- closure in the patent so as to enable the patent office and the public to determine quickly from a cursory inspection the nature and gist of the invention. The abstract appears on the front page of the published patent.

IX. PATENT CLAIMS The patent concludes with one or more claims that define the physical extent

or boundary of the exclusionary rights granted by the government to the patent owner. The claims also serve notice on the public as to what acts will

Patent Considerations 707 violate the personal property rights (infringement) as well as the physical

embodiments of the new knowledge that will come into the public domain upon expiration of the patent’s term.

The language of the claims follows certain prescribed rules. Each claim is one sentence as the object of the introductory ‘‘I (We) claim:’’ and con- tains three parts: the preamble, the transition and the body. The preamble is an introductory phrase that introduces the name of the subject matter and may include the purpose, object, or intended use of the invention. The preamble may also in some cases include elements of the prior art to segre- gate what is new or modified by the invention recited in the body of the claim. The claimed invention in this Jepson-type claim consists of the pre- amble elements combined with the new or improved elements for operabil- ity. Ordinarily, the preamble does not limit the scope of the claims and most patent practitioners avoid such limiting preambles. However, in some cir- cumstances a preamble has been deemed by a court to be significant to claim scope where terms appearing in a preamble gives meaning to the claim and properly defines the invention.

The second part of the claim, the transition, is the bridge between the preamble and the body of the claim and plays a major role in the interpreta- tion of the scope of the claim. Specific terminology for the transition has been adopted in patent practice to indicate whether the body of the claim should be read as open-ended or closed:

1. When the transition used is ‘‘comprises’’ (or ‘‘comprising, includ- ing, containing’’), the claim is to be interpreted as open-ended, i.e., the claim covers the elements (components, ingredients, steps) recited in the body of the claim as well as additional ele- ments. Thus the legal boundary is not limited only by the recited elements in the claim. A competitor cannot merely add an addi- tional element and avoid infringement. The term comprises can

be read as ‘‘having at least.’’

2. The transitional phrase ‘‘consisting of’’ indicates a closed-ended claim and the narrowest scope of coverage as the claim covers only the recited elements. A competitor can add an additional element and avoid literal infringement. This type of claim would only be used if necessary for operability or to avoid a novelty or obviousness rejection.

3. The transitional phrase ‘‘consisting essentially of’’ is intermediate in scope and is intended to exclude additional unspecified ele- ments that would affect the basis and novel characteristics of the subject matter recited in the body of the claim.

708 Roehrs The body of a claim recites the necessary elements required for the

invention to be operable and patentable over the prior art. Each element usually includes a well-defined name distinguishing it from other elements, distinctive features, or properties of the element necessary for operability and patentability, such as concentration range, and nature of cooperation, if any, with the other elements. The body of the claim can vary in scope as to how the elements are claimed: the narrowest scope names one specific com- ponent (ingredient) per element; an intermediate scope names a group of similar functionally equivalent components as the element; and the broadest scope names only the function that the element performs. These variations of course can be used only in light of their operability and patentability. The use of alternative expressions (Markush groups) can be a defined genus such as ‘‘halogen’’ or a homemade generic expression such as ‘‘chlorine or bro- mine.’’ The use of these groupings is considered closed-ended and is pre- ceded by the use of ‘‘consisting of.’’ An example of a functional claim element used in pharmaceutical compositions would be the element: ‘‘a pH-adjusting substance in an amount sufficient to adjust the pH to a value of from about 4 to 5.5.’’ The specification would contain examples describing a range of pH adjusting substances contemplated but not limiting in the practice of the invention.

A patent usually includes multiple claims, some of which are indepen- dent and some dependent. The claims are numbered consecutively, and the first claim is an independent claim of the broadest scope of the claimed invention, i.e., it contains the fewest limitations. It has the fewest elements in the broadest language consistent with operability and patentability. The dependent claims add an additional element or limitation and refers back to another claim or claims that it so modifies. If the invention covers a com- mercial product, there usually is a claim that is narrowed to recite all the specific elements of the product.

There may be claims to more than one statutory class of subject mat- ter. It is typical for drug delivery system patents to claim the delivery system (vehicle) as a composition of matter, claim the vehicle plus a pharmacolo- gically active drug, and also claim a method for using the delivery system to administer the drug. For claims reciting a drug as an element of the com- position of matter or method of use, it has become judicially acceptable to refer to the concentration of the drug as ‘‘a therapeutically effective amount.’’ For drug molecule patents, claims are usually included covering the drug, the drug in dosage form(s) usually claimed broadly as ‘‘pharma- ceutically acceptable carriers,’’ and methods for using the drug. Composition of matter claims are preferred over method of use claims since they would be in a dominant position to later patented new uses. Also, the person infringing a method of use claim is usually a customer.

Patent Considerations 709

X. PATENT EXAMINATION AND PROSECUTION Applications for U.S. patents are filed with the USPTO and examined by a

patent examiner in the art class to which the invention pertains. The examiner searches the prior art including U.S. patents, foreign patents, printed publications as well as his or her own personal knowledge of the art. The examiner is looking for references that show the identical inven- tion or prior art that can be combined or modified to demonstrate that the claimed subject matter would be obvious and thus unpatentable over the prior art.

The patent application will most likely contain pertinent prior art known to the inventor. In fact, each individual associated with the filing and prosecution of a patent application has a duty to disclose to the USPTO all information known to that individual to be material to patentability with respect to each pending claim. This duty of disclosure extends not only to the inventor(s) and the legal representative(s) but also to every other person substantially involved in the preparation and prosecution of the application and who is associated with the inventor, with the assignee, or with anyone to whom there is an obligation to assign. Individuals other than the inventor and legal representative can comply by disclosing the information to the inventor or legal represen- tative. The information may be disclosed in the patent specification or in a separate Information Disclosure Statement (IDS). An IDS is not construed as a representation that a search of the prior art was made or that no better art exists. This duty to disclose is satisfied if all informa- tion known to be material to patentability of any claim issued in a patent was cited by the patent office or submitted to the patent office. The front page of an issued patent contains a listing of references cited by the patent office as to U.S. patents, foreign patents, and other pub- lications. The front page of the patent also lists the classification of the patent’s subject matter and the field of search, i.e., the various subject matter classifications searched by the examiner.

The examiner will most likely issue an Office Action (OA) that sets forth any deficiencies in the application and allow or reject some or all of the claims. The examiner is required in the OA to set forth the basis and cite the best art available and how it applies to the claims that are rejected. The applicant can respond usually in the form of an amendment to traverse the rejections. This give and take with the examiner is termed ‘‘prosecution’’ of the application. The amendment may include an affidavit or declaration to remove a prior art reference used by the examiner to reject claims or to provide data and information as objective evidence of invention. Often the claims will be modified or narrowed to traverse a rejection and obtain an

710 Roehrs allowance. The prosecution continues until claims are allowed or a final

rejection is issued or the inventor abandons the application. In the case of

a final rejection, the inventor may appeal within the patent office and if unsuccessful to the courts. The prosecution of the application is conducted largely ex parte, i.e., in confidence between the USPTO and the inventor(s). The record of the pro- secution, i.e., the examiners papers as well as the application and the inven- tors responses to the patent office are kept in a folder that is termed a ‘‘file wrapper.’’ This file wrapper does not come with the printed patent but may

be obtained separately from the patent office. It is often useful to obtain to determine what information the inventor provided that may not be a part of the patent and what modifications may have been made to the claims during prosecution.

The first public knowledge of a U.S. patent application, unless dis- closed by the applicant or referred to in a published foreign patent applica- tion, had been the notification of an issued patent in the weekly Official Gazette published by the USPTO. However, since March 15, 2001, and subject to certain exceptions, regular nonprovisional utility patent applica- tions filed in the USPTO and also filed in a foreign country are being published 18 months after the effective U.S. filing date beginning with qua- lifying applications filed on or after November 29, 2000, and those pending on that date that request and qualify for voluntary publication. This change in U.S. patent law brings U.S. practice in alignment with most European countries and Japan that publish patent applications. To avoid publication of a pending U.S. patent application, the applicant must specifically request that the application not be published and certify that no foreign counterpart application will be filed. Certain applications subject to a secrecy order will not be published. The exception to publication of a patent application does not exist in European countries and Japan.

Once an application is published, the application and the complete file wrapper are publicly available. This provides the public with an early notice of potentially patentable subject matter, although it is no guarantee that a patent will be issued or the scope of the claims finally allowed. Also, it allows members of the public such as competitors to monitor patent prose- cution and to submit pertinent prior art for consideration by the patent examiner. The benefit to the inventor of having his or her pending patent applications published is the additional grant of so-called ‘‘provisional rights’’ to collect reasonable royalties for infringing acts prior to grant of

a patent as discussed in the next section.

Patent Considerations 711

XI. PATENT INFRINGEMENT The patent owner’s exclusive property rights may be violated (infringed) by

one or more of the acts of making, using, selling, offering to sell in the United States, or importing the patented invention into the United States. Some exceptions of interest to the pharmaceutical scientist are discussed below. The act of making or using the subject matter of at least one claim of a patent is sufficient for infringement. There does not have to be com- mercialization or intent to commercialize to commit an infringing act, but these are the usual reasons that a patent owner would sue for infringement. What is infringed is one or more claims of the patent, i.e., an embodiment of the invention and not the invention as a whole.

The question of whether an infringing act has been committed or whether infringement can be avoided is answered by focusing on the patent claims and their language in light of the patent specification, the prior art, and the prosecution history (file wrapper) of the patent. Literal infringement is determined by applying the claims to the suspect infringing product or process. If each and every element (limitation) of a claim exists in the suspect product or process, then there may be literal infringement. In patent jargon, the claim ‘‘reads on’’ the suspect product or process. If there are more elements in the suspect product or process and the claim is closed-ended by the transitional phrase used, then there may not be literal infringement.

The apparently straightforward interpretation of infringement can be complicated by the application of the judicially created Doctrine of Equivalents. Courts have in some cases, where the accused infringing pro- duct or process does not contain a limitation exactly as stated in a claim, extended the scope of the claim to interchangeable equivalents. Their rea- soning is one of equity to the patent owner, who must find language to describe the various embodiments of the invention as best he or she can while what is protected is the actual physical structure of the invention and not merely the words used in the patent. This judicial doctrine is somewhat controversial and can be legally complicated in its application. Courts usually apply a tripartite test when applying the doctrine in a specific case to determine if the element in issue performs substantially the same function in substantially the same way to achieve substantially the same result as the claimed element. The substantially equivalent element does not necessarily have to be described in the patent but may be something that the hypothe- tical person skilled in the art would consider interchangeable. The range of interchangeable equivalents may be determined from those available at the time of the infringement and not just at the time of the invention.

712 Roehrs When analyzing a patent for determining infringement or development

of a non-infringing product or process, the prosecution history in the patent office (file wrapper) should be examined. During prosecution of the patent application, the claims may have been modified or certain arguments may have been put forth to avoid a rejection of the claimed subject matter. In subsequent enforcement of patent rights, the patent owner cannot try to recapture subject matter relinquished during prosecution or change his posi- tion as to arguments made to avoid rejection. Subject matter relinquished such as by adding further elements or limitations to a claim is not part of the patent property and cannot be recaptured by the Doctrine of Equivalents.

With the publication of pending patent applications, provisional rights are granted that enable the patent owner to collect reasonable royalties for infringement during the period beginning on the date of publication of an application until the date the patent issues. However, these provisional rights are only available if the invention as claimed in the issued patent is substantially similar to the invention as claimed in the published patent application and proof is available that the alleged infringing party had actual notice of the published patent application.

Several specific exceptions to the law of infringement have been enacted by Congress. As discussed in Chapter 20, development and testing to obtain data for submission to FDA for marketing approval is not an act of infringement. This exception was made so that a drug patent’s limited monopoly would not, in effect, be extended if development of a generic product had to await patent expiration. The law makes the sub- mission of the marketing application prior to patent expiration the infrin- gement act.

Methods of diagnosis and treatment such as medical and surgical procedures performed on a body can and are patented as they qualify as statutory processes. Patent law was amended in 1996 (applies to patents granted on or after September 30, 1996) to preclude any remedy for infringement against a medical practitioner for his or her performance of a medical or surgical procedure. However, the exempted medical activ- ities do not include use of a patented machine, article of manufacture or composition of matter in violation of the patent, or the practice of a patented use of a composition of matter in violation of the patent, or the practice of a process in violation of a biotechnology patent. Also, the term ‘‘patented use of a composition of matter’’ does not include a claim for a method of performing a medical or surgical procedure on a body that recites the use of a composition of matter where the use of the composition of matter does not directly contribute to achievement of the objective of the claimed method. Thus, the exception is directed primarily to pure medical and surgical procedures where it is in the public interest

Patent Considerations 713 not to limit the use of innovative procedures because of the health care

professional’s concern for being sued for infringement.

XII.O PATENT SEARCHING In researching the patentability of an invention, it is important to know the

state of the prior art to which the invention pertains. Searching the prior art includes patents that have issued as well as printed publications in the non- patent prior art. While it is required to disclose to the USPTO material prior art known at the time the application is filed, it is not required by patent law that a search of prior art be made. However, it is beneficial to conduct as thorough a search of prior art as time and resources will allow. There are limitations on a patent search such that even the most thorough may not be 100% reliable in discovering all pertinent patented subject matter. Most patent searches focus on U.S. patents but may miss pertinent foreign patents, although the ability to search certain foreign patents using online databases is improving. There may be patent applications that have not been published, and patent databases that are searched may not be complete or some patents may have been misclassified.

In addition to searching for patentability, patent searches are under- taken to ascertain validity of issued patents such as in defense of an infrin- gement suit or to determine the right to use a prospective product (avoid infringement). Patentability and validity searches focus on expired and unexpired patents and published applications with a worldwide perspective while a right-to-use search focuses on unexpired patents and published applications in the United States and other countries of marketing interest. Another type of patent search is a state-of-the-art or collection search in which all patents and published applications in a particular area of technol- ogy are reviewed. The state-of-the-art search is particularly useful when beginning research in a new product area and can aid in avoiding duplica- tion of patented technology and focus efforts on improvements and new approaches.

Patent searching is usually conducted manually or electronically and increasingly by a combination of both methods using online patent data- bases. The availability of patent databases accessible through the Internet make it possible for the inventor to conduct at least a preliminary search for U.S. patents while in his or her lab or in the company or university library, just as he or she would conduct a literature search. These databases make it possible to keep up to date on new U.S. patents published on a weekly basis and published patent applications as well as some international applications

714 Roehrs and foreign patents. Specialized patent and research databases are being

developed in areas such as AIDS and biotechnology. The traditional manual method involves determining the most likely classification by the USPTO of the invention and then searching in these classes and subclasses for pertinent patents. This search may be done at the USPTO in Arlington, Virginia, where more than 6 million patents issued since 1790 are filed and can be manually examined. There is also a network of more than 80 Patent and Trademark Depository Libraries (PTDL) throughout the United States, most of which maintain a complete patent image collection on microfilm which is available for public patent searching.

A list of the locations of these PTDLs is available on the USPTO website at www:uspto:gov=go=ptdl. These patent libraries have complete information on U.S. patent classifications including a computer search system known as CASSIS on CD-ROMs from which a list of patents issued in each patent classification can be obtained. The bibliographic data from the front page of

a patent can also be accessed from CASSIS for utility patents issued since 1969. The front page of each patent includes the title of the invention as well as the patent abstract, which is often used to classify the subject matter of the invention. The front page also contains the patent classification, both U.S. and international, as well as references cited by the examiner. The references include U.S. patents, foreign patent documents, and printed pub- lications cited by the examiner as prior art. Some of the patent libraries also have access to the APS (Automated Patent System) text search program. The APS is connected by computer terminal to the patent database at the USPTO and enables searching the entire text of patents issued since August 1971. Several of these libraries also have an enhanced version of APS that allows viewing of patent images as well as text. Patent images are necessary to view the drawings contained in an issued patent.

The basic method for using the U.S. patent classification system to conduct a patent search involves compiling a list of classes and subclasses to search. This is done by making lists of words (terms) describing the impor- tant structural and functional features of the invention and first looking up the terms in the Index to the U.S. Patent Classification Manual (Index). The Index is an alphabetical listing of technical and common terms with corre- sponding U.S. patent classifications used by the USPTO. The classes and subclasses are numerical and written as, for example, 514/772, which sig- nifies Class 514 and its subclass 772. Second, once a list of potential classes and subclasses has been compiled, the Manual of Classification (Manual) is consulted, which lists all subclasses in an indented fashion under each main class in numerical order. The Manual aids in narrowing the classification to the most relevant subject matter. The Classification Definitions manual should then be consulted to further determine the relevance of the chosen

Patent Considerations 715 classes and subclasses for searching as it contains a description of the subject

matter for each class and subclass used by the USPTO. It also contains a cross-reference to other classification for similar subject matter and search notes explaining the scope and limits of a particular class or subclass.

If an inventor already has one or more patents in the same subject area as the prospective invention, he can begin classification searching using the U.S. classification(s) and Field of Search information listed on the front page of a patent. However, it is advisable to consult the USPTO classifica- tion documents referred to above, particularly for older patents, since the classification numbers may have changed or new class/subclass combina- tions may have been established. If the new invention contains new or different components, searching in additional classes and subclasses may

be required. Once a list of the most relevant class/subclass combinations has been obtained, the next step is to generate a list of patents issued in each class. The patent lists can be obtained using the CASSIS system or from online patent databases such as the USPTO. The lists contain the patent number and the patent title. It is usually necessary to review more than just the patent title to determine the most relevant patents that should be obtained for further review. The online databases usually have a link to the full text of the patent and a link to view the patent image (each page of the issued patent). Another means to review each patent from the list that may be relevant is the use of the Official Gazette that contains an exemplary claim and a representative drawing (if any) for each issued patent.

In reviewing a number of ophthalmic drug delivery patents, U.S. Classes 424 and 514 are frequently cited on the front page. The title of both classes is identical—‘‘Drug, Bio-Affecting and Body Treating Compositions’’—so these would be good places to begin a search. However, we need to narrow the search to specific subclasses, and we find in the Manual that classification 424/78.04 is listed as ophthalmic prepara- tions. Obtaining a list of patents in this classification indicates that of January 2002 there are 238 U.S. patents cited. In class 514 in the Manual we find that subclass 912 contains ophthalmic subject matter involving the treatment of an ophthalmic disorder, and a list of patents in classification 514/912 reveals 739 patents as of January 2002. Some of the ophthalmic patents in both classifications are obviously the same, but this example points out that there is no single classification for all ophthalmic drug delivery patents. For example, Class 427 is titled ‘‘Coating Processes,’’ and a number of pharmaceutical patents are contained in this class including ophthalmic drug and ocular devices. Also, Class 604, the Surgery classifica- tion, and subclass 890.1 include some patents directed to controlled release therapeutic devices or systems, a number of which relate to ophthalmic

716 Roehrs applications. Once relevant patent classifications have been established, the

search can continually be updated by periodically obtaining new lists of patents issued and published applications in these classifications. New patents are issued on a weekly basis, and these updates can easily be obtained by online patent database, discussed in the next section.

Another use of the online patent databases is to monitor competitor activity. Periodic updates of issued patents can be obtained for patent clas- sifications of research interest by searching in the current U.S. classification field. Monitoring can be enhanced by access to published foreign patent applications and the U.S. applications that are published. If there are certain companies and/or inventors that you want to monitor, this can be done by searching for issued patents for the company in the assignee field and the inventor (full name) in the inventor’s field. These fields are found on the front page of a patent.

The USPTO maintains an online patent database that can be searched without charge. The patent database contains full text of U.S. patents issued since 1790 hyperlinked to their full-page images. The database can be accessed from the Home page of the website at www:uspto:gov. The data- base can be searched in specific blocks of years or for all years (1790 to present). For the years 1790–1976, the database can be searched only by patent number and current U.S. classification. For patents issued from 1976 to present, keyword searches can be conducted on the full text. Advanced Boolean searches can be done in selected patent fields as well as multiple fields. Patent number searching is also available. Searching in specific class/ subclasses provides a list of issued patents with links to full-text and full- page images. The access to the image of each page of a patent allows examination of the drawings as well as the text. Special browser plug-ins or applications may be necessary to view the page images. The database contains a section that explains the contents and recent changes as well as missing or withdrawn patent numbers. It has Help functions that assist in most efficient use of the search functions and an Index to the site from which additional information available on the site can be obtained, for example, links to the three patent classification documents explained above. Patent documents can be ordered online for delivery in various forms for a fee.

Since March 15, 2001, the USPTO has been publishing certain patent applications, and these are available on their website in a separate database from issued patents. The published application database can be searched in essentially the same manner as the issued patent database. The published application database contains full-text and full-page images.

The Delphion Intellectual Property Network (formerly IBM) at www:delphion:com is a commercial online patent database. Due to a change in their business model in 2001, searching free of charge is now limited to

Patent Considerations 717 U.S. granted patents for certain years, and the free search is only conducted

on the front page (bibliographic information) of the patent. More extensive searching capabilities including published U.S. patent applications and cer- tain foreign published applications and granted patents are available now only by purchase of subscription packages. Copies of patent documents can

be ordered online and delivered in various forms for a fee. Many of the searching features are the same as at the USPTO site, but Delphion and other commercial fee–based patent databases have an advantage because they contain collections of certain foreign-published patent applications and issued patents, and the searching can be done in certain cases across the United States and international collections. The commercial sites may also offer prior art searching capabilities using technical journals and magazines. Commercial

include Micropatent (www:qpat:com).

BIBLIOGRAPHY The following publications were consulted in the preparation of the infor-

mation presented in this chapter:

1. The Patent Act of 1952, as amended, codified in Title 35 United States Code.

2. Title 37 Code of Federal Regulations. USPTO Rules and Regulations.

3. Manual of Patent Examining Procedure, USPTO, 1997.

4. Patent Law Basics, Rosenberg, Peter D., West Group, Release #9, July 2001.

5. The Law of Chemical and Pharmaceutical Invention, Rosenstock, Jerome, Aspen Law and Business, Second Edition, 2001 Supplement.

6. Patent Practice Handbook, Canelias, Peter S., Aspen Law and Business, 2001.

Index

Absorption Animal model, buffers, 6

rabbit vs. man, 61t, corneal factors, 60, 61, 70–72

Anterior chamber, of drugs

distribution of drugs, 151–158, 225 rate constant (k a ), 142, 143, 150t

microdialysis, 223 systemic, 109

Anterior segment, 109, 223, 323, 336 fraction absorbed, 148

pharmacokinetics, 226 mechanism, 2

Antibacterial agents, 313, 478 non-corneal, 336, 502

Antifungal agents, 322 nonproductive, 66–70, 142

Anti-inflammatory agents, 320, 321 productive, 65

Antimicrobial agents, 110 partition coefficient effect on, 5, 62,

quinolone, 126 64, 350

Antisense drugs, 582, 629 pharmacokinetic modeling, 144–151

Antiviral agents, 324, 478 rate constants, 70, 71t, 149, 150t

Aptamers, 640 vehicle effect on, 351

Aqueous humor, 313 Acquired immunodeficiency

clearances, 79t syndrome, 110, 251

dynamics, 224 Adsorption, 412, 445

elimination half-lives, 78t Age-related macular degeneration,

sampling, 138 537

Arginine vasopressin (AVP), 494 Aldose reductase inhibitors, 42 Alkali burn, 326

Bandage soft contact lenses, 309 Anesthesia, 376

Bardet-Biedel syndrome, 540

720 Index Barriers

Choriodermia, 540, 618 blood-aqueous, 8, 26, 37, 111–114,

Choroid, 181, 253 251, 260, 441

Ciprofloxacin, 381 blood-ocular, 8, 111–114, 438

Coloumb’s law, 366 breakdown of, 113, 114

Collagen,

drug transport across, 42 cross-linking, 311 structure and function, 112, 113

inserts, 310 blood-retinal, 8, 34, 37, 92, 251,

properties, 310 254, 260, 441

shields, 310, 312, 320 endothelium, 9, 37

clinical studies, 326 epithelium, 9, 34

properties, 311 integrity, 259

Cones, 516

Basic fibroblast growth factor Confocal microscopy, 341 (bFGF), 523

Conjunctiva, 23, 281, 318 Bassen-Kornzweig syndrome, 540

anatomy, 338 Benzalkonium chloride (BAC), 64

epithelium, 24 Beta-adrenergic antagonists

inserts, 352 (blockers), 424, 343

permeability, 349, 350 absorption, 233

transmembrane electrical resistance, disposition, 233

17t

ocular membranes permeability, Conjunctivitis, 13, 369 349t

Conscious animal model, 236 pharmacodynamics, 240

Contact lenses, 309 Betoptic S, 455

Cornea, 281, 497 Bioadhesion (see Mucoadhesion)

absorption, 141 Bioadhesives, 281, 301, 409, 440

kinetics, 70, 71t Bio-Cor, 311

barriers, 4 Blanching, 374

diameter, 51t, 137t Bowman’s membrane, 4, 19, 20

endothelium, 3, 5, 21 Brain-derived neurotrophic factor

epithelium, 20, 313, 325 (BDNF), 585

ion and organic solute transport, 21 Brij-78, 506, 507

penetration, 61 Bruch’s membrane, 36, 253

permeability coefficients, 285t Butyrlcholine esterases, 93, 161

permselectivity, 284 surface area, 51t,

Canal of Schlemm, 3, 224 thickness, 51t, 137t Candida albicans, 322

transmembrane electrical resistance, Capsid, 570

17t

Carbonic anhydrase inhibitors, transplantation, 309 Carbopol, 415t

transport characteristics, 283 Carboxymethyl cellulose, 415t

paracellular, 4 Cefazolin, 269, 383

transcellular, 5 Cell culture, 346

Corneal

Cellulose acetate phthalate, 425 peptide permeation, 496, 497 Cephalosporins

permeability pharmacokinetics of, 268

effect of concentration, 6

Index 721 [Corneal]

Drug delivery systems effect of molecular weight, 349t

inserts, 424 effect of partition coefficient, 5,

liposomes, 423 (see also Liposomes) 63, 64, 342, 349, 350

microparticles and nanoparticles, paracellular permeation, 347

352, 637 (see also Corneoscleral limbus, 368

Nanoparticles and Cul-de-Sac, 2, 8, 338

Nanospheres) Cyclosporin A, 323, 324, 444, 503

Drug distribution, 77, 83 nanocapsules, 452

microspheres and nanospheres, 426, Cystic fibrosis, 483, 561

439, 444, 445 Cytochalasins, 295, 507

pharmacokinetic modeling, 86, Cytomegalovirus retinitis, 251, 384

151–158 foscarnet, 384

vitreal

intravitreal ganciclovir, 271 injection position, 84, 196 intravitreal therapy, 254

injection volume, 84 phakic and aphakic eyes, 85

Dendrimers, 467–486,

Dry eye, 329

chemical structure and synthesis of, 469–471

EDTA, 288

convergent process, 471 Efflux, 110, 113 divergent process, 470, 471

pumps, 40

PAMAM, 469–474 Elimination, 140 core, 472, 473

drug, 77, 83, 158 physical properties, 472

kinetics, 158, 159 surface, 473, 474

Embryonic germ cells (EG), 553 therapeutic uses,

Embryonic stem cells (ES), 553 drug delivery, 475–480

Endocytotic stimulator, 301 gene therapy, 480–483, 625

Endophthalmitis, 109, 260, 441 ocular therapy, 484–486

postoperative, 251 tissue distribution, 474, 475

treatment, 353 Descemet’s membrane, 19, 20, 328

Enhanced paracellular transport, 288 Device, 671

Enhanced transcellular transport, 296 Dexamethasone, 378, 524

Enkephalin

Diabetic retinopathy, 516 leucine, 503 Dialysis

methionine, 503 principles of, 228

Enzyme, 162

Diffusion, 2 carboxycholine esterases, 93, 162 across conjunctiva, 338

cytochrome P450, 93 Fick’s law, 5, 228

peptidases, 93 across sclera, 339

Epidermal growth factor, 325 in vitreous (Davis equation), 206

Epithelium

Direct aspiration, 117, 118 ion channels, 21, 25, 28, 32, 38 Dose-response curves, 95, 165

lipid content, 3 DOPE, 579

routes of transport, 15 Drug, 670

TEER, 284 product, 681

transport characterstics, 283

722 Index [Epithelium]

Human growth hormone, 499 transporters, 15

Hyaluronic acid, 206 Eye, 226

Hydrogel, 206 anatomy, 337

Hydroxypropymmethylcellulose, 425 Hyloid membrane, 182, 191

Faraday’s law, 367 Hyperhiderosis, 370 Federal drug laws, 664 Fluorescein, 193, 194, 206, 313

Immunosuppressive agent, 323 angiography, 543

IND application, 674 Fluorescein glucuronide, 187

Indocollyre, 453 Fluorophotometry, 69, 86, 226

Infection and treatment, 378 Formivirsen (ISIS 2922), 584

Inflammation, 377 Fovea, 516

Information disclosure statement (IDS), 709 Gamma scintiography, 68

Injections, 441 Ganglion cells, 516

intracameral, 159, 234 Gene therapy, 559, 610

intravitreal, 83–88 adeno-associated virus vector, 575,

distribution in phakic 613

and aphakic eyes, 85 adenovirus, 570, 613

factors affecting, 182 applications, 560

pharmacokinetics, 86 gene gun, 622

position, 196–204 lentivirus, 616

side effects, 83 lipid mediated drug delivery, 635

volume, 84 liposome, 622

subconjunctival, 90, 321, 323 naked DNA, 578, 621

subtenon, 91 nonviral vectors,

Insulin delivery, 501 peptides, 624

Integration-induced mutagenesis, polycations, 635

retrovirus,565, 612 Interpenetration theory, 412, 413 viral-vector–mediated, 611

Inulin delivery, 502, 505 Gentamicin, 378

Investigational new drug (IND), 672 pharmacokinetics of, 263

Iontophoresis, 365 Glaucoma, 373

applications, 369 adrenergic agents, 375

basic concepts, 365 5-fluorouracil, 376

design of devices, 367 Glial-derived neurotrophic factor, 545

dexamethasone, 377 Gonioscopic approach, 374

epinephrine, 391 Good laboratory practices, 680

foscarnet, 386 Good manufacturing practices, 683

lidocaine of, 371, 377 Growth factors delivery, 503

pilocarpine of, 370 Gyrate atrophy, 540, 610

protein absorption, 497 transcorneal, 371

Herpes simplex virus, 110, 386, 576 transcutaneous delivery, 369 keratitis, 110

transscleral, 371 treatment, 386

Iris, 25, 28

Index 723 Ischemia, 526

[Microdialysis] posterior segment, 251 Junctional complexes, 284

principles, 228 probe design, 227, 229, 256

Keratitis, 13 recovery 229–232, 258 bacterial, 313, 320

absolute recovery, 231 pseudomonas, 318, 319

difference method, 231 viral, 386

no-net flux method, 231 Keratoconjunctivitis sicca, 419

perfusion rate method, 232 Keratomycosis, 322

relative loss method, 231 Ketoconazole, 383

relative recovery, 231 Ketone reductase, 93

water recovery method, 231 Microparticles and microspheres (see Lacrimal drainage, 437

also Drug delivery systems): Lacrimal fluid, 61t

adriamycin, 456 Lacrimation, 281

albumin, 455 Laser sclerotomy, 374

5-fluorouracil, 456 Latanoprost, 156

gelatin, 455 Latency associated transcripts, 391

production (see Nanoparticles) Leber congenital Amaurosis, 539

Minimum bactericidal concentration, Lens, 30

epithelium, 32, 158 Minimum inhibitory concentration fiber cells, 34, 158

(MIC), 313, 320, 328 iontransport, 32

oxidative balance, 34 conscious, 236 Lipoproteins, 624

cationic, 579 dog, 522 coated, 426

knockout mouse, 519 DNA transfer, 578

natural mutation mouse, 517 ligand-targeted, 580

rat, 520

problems associated, 439 transgenic mouse, 518 stealth liposomes, 580

transgenic pig, 521 sustained release, 423

metabolic, 159 Lysine vasopressin, 494

neovascularization, 525 pharmacokinetic, 120–123, 144, 236

Macula, 516 physiological, 81 edema, 109

vitreal, 86 Macular degeneration, 517, 537, 538

retinal degeneration, 522 Macular occludens, 21

vitreal drug disposition, 80 Microdialysis, 118–119, 252, 255

Araie and Maurice, 183 advantages, 256

effect of apahakia, 205 anterior segment, 226

finite element, 186 dual-probe, 237

Ohtori and Tojo, 185 perfusion flow rate, 257

Yoshida, 184

724 Index Mucoadhesion, 440

Noncorneal pathway, 3 mechanism of, 412–414

barriers, 338 vehicular effects on, 420–422

b -blockers, 342, 343 polyacrylic acid (PAA), 421 polyvinyl pyrrolidine, 421

Ocular absorption, 62 Mucoadhesive polymers:

mechanisms, 2 characterstics of, 414–416

Ocular bioavailability, 67t, 318 contact time, 417, 419

Ocular

drug incorporation in, 419, 420 clearances, 79t hydration degree, 415, 416

drug transfer, 109–127 natural, 427

infection (see Infection) pH and, 416, 417

inserts, 437 phase transition, 425

metabolism, 92 synthetic, 428, 429

protein delivery, 495, 500 Mucus, 410

Ocular penetration, 114–116, 123 composition, 410

physicochemical properties hypersecretion, 419

affecting, 114–116 hyposecretion of, 419

Ocular pharmacodynamics, 94–97, mucin, 410–412

125, 164 Muller cell, 515

Ocular pharmacokinetics, 60–93, Multidrug resistance-associated

116–127, 233 protein, 42

absorption, 148 absorption phase, 141

Naı¨ve pooled data approach, classical modeling in, 136, 144 116–117

limitations of, 136 Nanoparticles and nanospheres (see

distribution, 151 also Drug delivery systems)

distribution phase, 142 distribution, 449

elimination, 158 drug release, 446

elimination phase, 140 drugs used in, 451

intravitreal administration, 83 polymeric, 445

modeling, 144 production, 442

periocular administration, 88 emulsion polymerization, 442

sampling times, 140 interfacial polymerization, 443

systemic administration, 92 ionic gelation, 444

topical administration, 60 nanoprecipitation, 444

absorption in, 60 solvent evaporation, 443

Ocular pharmacology, 240 spray-drying, 444

Ohm’s law, 366 transport pathway, 447

Oligodeoxy nucleotides, 582 Nasolacrimal occlusion, 68

Oligonucleotide therapy, 627 Neovascularization, 525

Ora serrata, 253 Neural retina, 515 Neurotrophic factors, 586

Paracentesis sampling, 226, 260 New drug application (NDA), 672

Particulate drug delivery, 439 content, 684

Patent, 695

Nictitating membrane, 61, 131, 226 applications, 704

Index 725 [Patent]

Polycarbophil, 344, 352 claims, 706

Polycyanoacrylate (PACA), 443, 445, examinations and prosecution, 709

rights, 696 Polylactide-co-glycolide, 444 specifications, 705

Polymerization, 442, 443 term, 697

Polymethylmethacrylate (PMMA), 445 Patent and Trademark Depository

Population pharmacokinetics, Libraries (PTDL), 714

123–125 Patentable inventions, 698

Posterior segment Penetration enhancers

anatomy, 252 kinetics, 282

diseases affecting, 2 mechanism, 287

distribution to, 76 new, 296

microdialysis, 251 Azone, 297

volume, 252 cyclodextrin, 296

Precorneal

Saponin, 298 constraints, 9 novel, 298

drainage, 66-69 -aminoacid, 298

fluid dynamics, 338 Pz-peptide, 300

Prodrugs, 159, 161 percutaneous, 297

acyclovir, 9 polymeric, 301

ganciclovir, 9, 271 chitosan derivatives, 302

idoxuridine, 5, 159 polyacrylates, 301

phenylephrine, 92, 95, 159 Peptide

pilocarpine, 92, 159 carrier/transporter, 9, 271

timolol, 63, 92, 159 drugs, 493, 494, 501

tromethamine, 92 Periocular administration, 88-91

Proliferative vitreoretinopathy, 569 subconjunctival, 90

animal models, 523 subtenon retrobulbar, 91

microparticles in, 441 Permeability (see also Corneal

retinal detachment in, 517 permeability)

Prostaglandin PGF , 2, 156 conjunctiva, 344, 349

Protein binding, 115 retinal, 182

Protein delivery, affect of aphakia, 205, 208, 217

buccal, 495, 499, 500 fluorescein, 192t, 193, 194

nasal, 495, 499 sclera, 344, 347

ocular, 495, 500 P-glycoprotein, 26, 41

oral, 495, 498, 499 Phonophoresis, 497

pulmonary, 495, 500 Pigment epithelium derived factor

Protein drugs, 493, 494, 501 (PEDF), 572, 588

Pseudomonas areuginosa , 318 Pilocarpine

Pupillary response, 6 absorption rate constant, 150t effect of buffer, 6 nanoparticles, 451, 452

Regulatory requirements volume distribution, 74t, 153t

clinical studies, 674 Piloplex, 452

drug vs. device, 670

726 Index [Regulatory requirements]

Stem cell transplant, 552 federal vs. state regulation, 674

Sterilization, 682 human vs. animal testing, 673

Stroma, 4

new drug, 672 disease treatment, 387 Retina, 9, 515, 555

Subconjunctival injection (see also degenerative diseases, 536

Injections), 254 layers in, 34

Subtenon and retrobulbar injection transporter, 9

(see Injections) Retinal

Suicide genes, 569 blood vessels, 37

Systemic

degeneration slow, 589 administration, 109 detachment, 83, 516

loss, 339, 344 traction, 517 disease models (see also Models)

t 1/2

515 absorption, 71t, 152t inflammation, 84

vitreous, 85t, 86 implants, 541

subretinal, 556 fluid dynamics, 338, pigment epithelium (RPE), 35, 112,

milliosmolality, 61t 515

pH, 137t

TEER, 17t turnover rate, 61t, 338 tight junctions, 36

volume, 61t, 338 transplant, 540, 541, 546

Tenon’s capsule, 91 Retinitis pigmentosa, 517, 538, 539,

Tight junctions, 4, 16, 284 563, 617

blood ocular barrier in, 9 Retinoblastoma, 517

corneal epithelium in, 21 Retinopathy of prematurity, 516

RPE, 36

Retrobulbar injection, 91 Timolol, 344, 352 (see also Prodrugs) Rhegmatogenous detachment, 516

pharmacokinetics, 233 Rhodopsin, 518

Tobramycin, 381 Ribonuclease

Tonography, 227 H, 627

Topical ocular administration, 60, 281 P, 585

infusion, 150, 151 Ribozymes, 584, 641

Trabecular meshwork, 225 group I and group II intron, 584

Transepithelial electrical resistance hammer head, 584

(TEER), 284 Rod/cone dysplasia, 521, 522

Transport

calcitonin, 506 Sclera, 253, 339

protein, 496 permeability, 348

Pz-peptide, 504 Scleral implant, 353

Transporters, 18 Scleritis, 109, 369

Trifluorothymidine, 324 Serial sampling, 138, 255 Soft drugs, 162

United States Food and Drug Staphylococcus areus , 319

Administration (FDA), 664

Index 727 United States Patent and Trademark

[Vitreous]

Office (USPTO), 697 drug distribution in (see Drug Uveitis, 109

Distribution) endotoxin-induced, 114

physiology, 181 recurrent, 441

Volume of distribution, 72, 74t, 152 Uveoscleral route, 224

Vancomycin, 382

Zonula

Vitrectomy, 110 adherens, 17, 36 Vitreous, 441

occludentes, 4 composition of, 206

Zonulae, 26