In 1978, the FDA Commissioner announced the FDA’s intent to provide a list of all prescription drug products approved by the FDA for safety and effectiveness under the Federal Food, Drug, and Cosmetic Act (FD&C Act). This list evolved into the current Orange Book. It included and continues to include only prescription drug products approved by the FDA and marketed at the time of publication. The main criterion for the inclusion of a product is that it has a new drug application (NDA) or abbreviated new drug application (ANDA) that has been approved by the FDA and that has not been withdrawn for safety or efficacy reasons. A first version of the list was published on Oct. 31, 1980. The current version can be found on the FDA’s website at Approved Drug Products with Therapeutic Equivalence Determinations, http://www.fda.gov/cder/ob/default.htm.

The Drug Price Competition and Patent Term Restoration Act of 1984 (Hatch-Waxman Amendments) became law on Sept. 24, 1984. The Orange Book and its monthly supplements satisfy the Hatch-Waxman requirement that the FDA provide a publicly available list of approved drug products.

The Hatch-Waxman Amendments ushered in the current Orange Book by establishing a special system for pharmaceutical patent infringement litigation involving non-biologic, small molecule drug products and methods of using the same.[1] The Hatch-Waxman Amendments represent a compromise between the patent owners/innovators and generic drug manufacturers. For the patent owners, the Hatch-Waxman Amendments provide patent term restoration (often referenced as patent term extension), marketing exclusivities, a 30-month litigation stay, and pre-market patent litigation decisions. Generic manufacturers received the expedited ANDA approval process, 180-day exclusivity for the first ANDA filer, a safe harbor from infringement for bioequivalence testing, and pre-market patent litigation decisions. The Orange Book provides the vehicle through which the system established by the Hatch-Waxman Amendments operates.

To list in the Orange Book, an NDA holder/patent owner timely submits Forms 3542a and 3542 to the FDA. Form 3542a is filed along with the New Drug Application (NDA), and Form 3542 is filed after FDA approval has occurred. The focus of this article is on Form 3542, calling out areas for improvement to facilitate proper listing.

The impetus for this article is found in the FDA’s recent request for comments about the Orange Book “as part of an Agency wide effort to modernize the Orange Book.” See 85 Fed. Reg. 33,169 (June 1, 2020). The FDA is “examining whether [it] should further evaluate or provide additional clarity regarding the types of patent information listed in the Orange Book. Id. at 33,172-73.

As long time practitioners, we provide our suggestions for improvements to Form 3542 with accompanying explanations. These materials have been prepared solely for educational purposes to contribute to the understanding of U.S. intellectual property law. These materials reflect only the personal views of the authors and are not individualized legal advice. It is understood that each case is fact specific, and that the appropriate solution in any case will vary. Therefore, these materials may or may not be relevant to any particular situation. Thus, the authors and Finnegan, Henderson, Farabow, Garrett & Dunner, LLP (including Finnegan Europe LLP, and Fei Han Foreign Legal Affairs Law Firm) cannot be bound either philosophically or as representatives of their various present and future clients to the comments expressed in these materials. The presentation of these materials does not establish any form of attorney-client relationship with these authors. While every attempt was made to ensure that these materials are accurate, errors or omissions may be contained therein, for which any liability is disclaimed.

And to reemphasize a point made above, these suggested revisions assume that only small molecules remain the subject of Orange Book listings; there is no suggestion to open the Orange Book to listing biologics or subject matter otherwise covered by the BPCIA. The revisions also assume the format of Form 3542 remains even though our preference would be to eliminate the “box-checking” within Form 3542 and substitute it with a simple listing of patents, representative claims, patent type and use description. That preference may well, however, require action by the United States Congress and the President. Hence, at the moment, we prefer to retain the Form 3542, but in a version modified as suggested herein.

Section 2.1 Does the patent claim the drug substance that is the active ingredient in the drug product described in the approved NDA or supplement? If yes, skip to Question 2.5.

Rewrite 2.1 as: Does the patent contain at least one claim that is to the drug substance in the drug product described in the approved NDA or supplement?

Remove “skip to Question 2.5”

Why: Generally, we oppose being automatically skipped from one box to another. Also, one would not necessarily go to 2.5 after answering yes to 2.1. For instance, if the only basis for listability is at least one claim directed to a different polymorph of the drug substance described in the approved NDA or supplement, then both 2.1 and 2.2, below, should be answered yes, and 2.3 and 2.4 should be addressed before addressing 2.5. But, if there is a claim to the approved drug substance and no additional claim directed to a different polymorph of the drug substance described in the approved NDA or supplement, then 2.1 is yes and 2.2 is no. In that case, 2.3 and 2.4 would be not applicable, and one would move to 2.5.

Section 2.2 Does the patent claim only a drug substance that is a different polymorph of the active ingredient described in the NDA?

Rewrite 2.2 as: Is the only basis for listability of the patent at least one claim in the patent directed to a drug substance that is a different polymorph of the drug substance described in the approved NDA or supplement, even if you answered yes to 2.1? If yes, go to 2.3 and 2.4. If no, go to 2.5.

Why: The use of “only” in present 2.2, is confusing. What a patent “claims” is determined by the plain language of the claims of the patent. This revision makes clear that the answer to 2.2 is “Yes” if at least one claim in the patent is directed to a different polymorph of the drug product described in the approved NDA or supplement and if that at least one claim is the only basis for listability of the patent. And as noted above, if the at least one claim is the sole basis for listability, then answer both 2.1 and 2.2 yes.

Section 2.3 If the answer to question 2.2 is “Yes,” do you certify that, as of the date of this declaration, you have test data demonstrating that a drug product containing the polymorph will perform the same as the drug product described in the NDA? The type of test data required is described at 21 CFR 314.53(b).

Rewrite 2.3 as: If the answer to question 2.2 is “Yes,” do you certify that, as of the date of this declaration, the NDA holder and/or the Patent Owner has test data demonstrating that a drug product described in the approved NDA or supplement and containing the polymorph, wherein the polymorph is different from the drug substance described in the approved NDA or supplement, will perform the same as the drug product described in the NDA? The type of test data required is described at 21 CFR 314.53(b).

Proposed revision to 21 CFR 314.53 (b), referenced just above in 2.3:

(2) Test data for submission of patent information for a patent in which the only basis for listability of the patent is at least one claim in the patent directed to a drug substance that is a different polymorph of the drug substance described in the approved NDA or supplement. The test data, referenced in paragraph (b)(1) of this section, must include the following:

(i) A full description of the polymorphic form of the drug substance, including its physical and chemical characteristics and stability; the method of synthesis (or isolation) and purification of the drug substance; the process controls used during manufacture and packaging; and such specifications and analytical methods as are necessary to assure the identity, strength, quality, and purity of the polymorphic form of the drug substance;

(ii) The executed batch record for an executed batch of a drug product containing the polymorphic form of the drug substance and documentation that the batch was manufactured under current good manufacturing practice requirements; the executed batch record comprises the executed manufacturing instructions containing the complete documentation of all activities and measurements associated with production of a Lot of bulk drug product, i.e, the executed batch.

(iii) Demonstration of bioequivalence between the executed batch of the drug product that contains the polymorphic form of the drug substance described in the approved NDA or supplement and the drug product as described in the NDA or supplement and not containing the polymorphic form of the drug substance. See 21 CFR 314.94(a)(7).

(iv) A list of all components used in the manufacture of the drug product containing the polymorphic form and a statement of the composition of the drug product; a statement of the specifications and analytical methods for each component; a description of the manufacturing and packaging procedures and in-process controls for the drug product; such specifications and analytical methods as are necessary to assure the identity, strength, quality, purity, and bioavailability of the drug product, including release and stability data complying with the approved product specifications to demonstrate pharmaceutical equivalence and comparable product stability; and

(v) Comparative in vitro dissolution testing on 12 dosage units each of the executed test batch (test product) and the product described in the approved NDA or supplement (reference product). Executed test batch is referenced in (ii) above. For in vitro dissolution testing methods, see http://www.accessdata.fda.gov/scripts/cder/dissolution. Also, an applicant must characterize comparative dissolution testing using at least 12 dosage units each of test and reference products, whether it proposes to use a USP method, an FDA-recommended method, or its own method. In cases where the applicant develops their own method, both data using their method as well as data from the FDA-recommended method should be submitted for comparison.

Why? The idea is to clarify what is meant by bioequivalence, in vitro dissolutions, and executed batches; concepts which require specificity for the patent professionals who are often tasked to fill out Form 3542.

Section 2.4 Specify the polymorphic form(s) claimed by the patent for which you have the test results described in 2.3.

Rewrite 2.4 as: Specify the polymorphic form(s) recited in at least one claim of the patent which formed the only basis for listability of the patent and for which you have the test results described in 2.3. The NDA holder/patent applicant will have given a complete description of the polymorph(s) in 314.53(b)(2)(i) above, so simply identify the polymorph(s) as set forth in Section 2.3 in such at least one claim.

Section 2.5 Does the patent claim only a metabolite of the approved active ingredient? (Complete the information in section 4 below if the patent claims an approved method of using the approved drug product to administer the metabolite.) 

Rewrite 2.5 as: Are all of the claims in the patent that are being relied upon for listing the patent in the Orange Book as covering the approved drug substance directed to a metabolite of the drug substance as described in the approved NDA or supplement? Drop the parenthetical “(Complete the information in Section 4 below, if the patent contains at least one claim directed to an approved method of using the approved drug product to administer the metabolite)” which is very confusing. If relevant, that parenthetical information will be subsumed in Section 4.1. Also drop the confusing use of “claim only a metabolite”.

Why: What a patent “claims” is determined by the plain language of the claims of the patent.

This revision makes clear that the answer to 2.5 is “Yes” only if all claims that form a basis for listability of the patent are directed to a metabolite of the approved drug substance described in the approved NDA or supplement. But if 2.5 is yes, then 2.1 must be no. If the answer to 2.5 is no, then there might be other claims providing a basis for listability of the patent.

Section 2.6 Does the patent claim only an intermediate? 

Background:

In GFI#126-BACPAC 1: Intermediates in Drug Substance synthesis, intermediate is defined at p. 22 as: “A material produced during steps of the synthesis of a drug substance that undergoes further molecular change before it becomes a drug substance.” See also: Intermediate defined as: “A material produced during the steps in the synthesis of an API that must undergo further molecular change or processing before it becomes an API. Source: https://www.pharmaguideline.com/2011/09/terminology-definitions-in.html#gsc.tab=0”

Hence, for FDA, an intermediate is NOT a drug substance but is a synthetic compound that undergoes further molecular change before it becomes a drug substance.

Rewrite 2.6 as: (drops the confusing phrase “claim only an intermediate.”) Are all claims in the patent directed to a non-drug substance, synthetic intermediate of the drug substance described in the approved NDA or supplement, and are those claims the only basis for listability of the patent? If so, the correct answer is yes. But assume that all claims providing the basis for listability of the patent are directed to a drug substance, not a synthetic intermediate, that upon formulation, such as tabletting, or storage, converts to the approved drug substance described in the approved NDA or supplement. If so, the patent is to be listed under Section 2.1 above and the answer to 2.6 is no. Conversely if a patent is not listable under 2.1, 2.6 does not apply.

Section 2.7 If the patent referenced in 2.1 is a product-by-process patent, is the product claimed in the patent novel? 

Delete 2.7.

Why: If all claims, even though they are in product-by-process form, are listed based on 2.1, then the drug substance(s) claimed must be novel in accord with Abbott v. Sandoz, 566 F.3d 1282 (Fed. Cir. 2009) (en banc) and Atlantic Thermoplastics Co. v. Faytex Corp., 970 F.2d 834 (Fed. Cir. 1992), holding that process limitations are not taken into account in assessing the patentability of the product in a product-by-process claim. Otherwise, the claims of the patent could not, or at least should not, have issued. Hence, 2.7 is rendered redundant and can be eliminated.

Summary of Section 2

FDA will not list the patent in the Orange Book as claiming the drug substance if:

  • the answers to 2.1 and 2.2 are “No,” or,
  • the answer to 2.2 is “Yes” and the answer to 2.3 is “No,” or,
  • the answer to 2.3 is “Yes” and there is no response to 2.4, or,
  • the answer to 2.5 or 2.6 is “Yes.”
  • the answer to 2.7 is “No.”

Delete the last line, referring to 2.7; it is redundant to 2.1

Section 3.1 Does the patent claim the approved drug product as defined in 21 CFR 314.3? 

Rewrite 3.1 as: Does the patent contain at least one claim that is the drug product described in the approved NDA or supplement? If so, the answer is yes.

Section 3.2 Does the patent claim only an intermediate?

Rewrite 3.2 using the same reasoning and same language as 2.6 above.

Section 3.3 If the patent referenced in 3.1 is a product-by-process patent, is the product claimed in the patent novel? 

Delete 3.3 for the same reasons given above for Section 2.7.

Summary of Section 3

FDA will not list the patent in the Orange Book as claiming the drug product if:

  • the answer to question 3.1 is “No,” or,
  • the answer to question 3.2 is “Yes,” or,
  • the answer to 3.3 is “No.”

Delete the last bullet, as we propose to delete section 3.3.

Notably, before Section 2, Form 3542 says:

  • If the patent is eligible for listing as claiming the drug substance and section 2 is completed, it is not necessary to complete section 3 even if the patent also is eligible for listing as claiming the drug product.
  • If the patent is eligible for listing as claiming the drug product and section 3 is completed, it is not necessary to complete section 2 even if the patent also is eligible for listing as claiming the drug substance.

However, it is still important to retain both Sections 2 and 3, as proposed to be revised herein, in Form 3542 because there may be claims listable under Section 3 that are not listable under Section 2. For example, assume a patent has claims directed to hydroxychloroquine (known for decades) and a novel formulation for enhancing bioavailability of the hydroxychloroquine in a patient infected by COVID-19. It is not clear how such a patent could be listed under Section 2, but it could be listed under Section 3. And the patent owner might find a 35 USC 112(f) claim to be particularly helpful to avoid skinny labeling under Section 4 and to cover hydroxychloroquine and all literal equivalents set forth in the patent in combination with the novel formulation.

Section 4 METHOD OF USE

NDA holders must submit the information in section 4 for each approved method of using the approved drug product claimed by the patent. An NDA holder may list together multiple patent claims for each approved method of use; however, each approved method of use claimed by the patent must be separately identified within this section. Continuation pages may be used to separately list method of use information within this section. For each approved method of use claimed by the patent, provide the following information:

Section 4.1  Does the patent claim one or more approved methods of using the approved drug product? (Select one) ___ Yes (only one approved method of use ___ Yes (more than one approved method of use ___ No

Rewrite 4.1 as. For the “Yes” boxes, make the first read Yes (patent claims only one approved method of use) and make the second read Yes (patent claims more than one approved method of use).

Add in the immediately preceding paragraph regarding responding to Section 4.1: “Similarly, if the patent claims only one approved method of use, complete Fields 4.2, 4.2a, and 4.2b.

Also add the following helpful information from the Form 3542 instructions to 4.1:

If you answer yes to question 4.1, you are also required to state whether the patent also claims the drug substance or drug product. Accordingly, make sure you have completed section 2 or section 3, if appropriate.

If the patent claims more than one approved method of use, separately identify and complete Fields 4.2, 4.2a, and 4.2b for each approved method of use claimed by the patent. Click the “Add section 4.2” button to add a new set of section 4.2 entries for each approved method of use claimed by the patent.

Further proposal: specifically note that the “Add section 4.2” button is at the end of Section 4.

Section 4.2  Patent Claim Number(s) (as listed in the patent) (Please separate numbers with commas.)

Does (Do) the patent claim(s) referenced in 4.2 claim an approved method of use of the approved drug product?

Rewrite 4.2 as: Delete right side of the box.

Section 4.2a  If the answer to 4.2 is “Yes,” for each approved method of use, separately identify the specific section(s) and subsection(s) of the approved labeling for the drug product that describe the approved method of use claimed by the patent. If there is no applicable subsection, insert “subsection N/A”. If there is more than one approved method of use, please use the “Add Section 4.2” button for additional entries as needed.

Use (In your answer below, please list each section on a separate line. Within each line, separate each subsection with a comma.)

Rewrite 4.2a in one box as: For each approved method of use, separately identify the specific section(s) (please list each section on a separate line and within each line, separate each subsection with a comma), and subsections(s) of the approved labeling for the drug product that describe the approved method of use claimed by the patent. If there is no applicable subsection, insert “subsection N/A”. If there is more than one approved method of use, please use the “Add Section 4.2 button for additional entries as needed.

Section 4.2b  If the answer to 4.2 is “Yes,” also provide the information on the approved method of use claimed by the patent for the Orange Book “Use Code” description.

Use (Submit the description of the specific approved method of use claimed by the patent that FDA should include as the “Use Code” in the Orange Book, using no more than 250 total characters including spaces.)  

Rewrite 4.2b in one box as: For each approved method of use, provide the description of the specific approved method of use claimed by the patent that FDA should include as the “use code” in the Orange Book. Each use code must describe only an approved method of use claimed by the patent for which a claim of patent infringement could reasonably be asserted if a person not licensed by the patent owner engaged in the manufacture, use, or sale of the drug product. In other words, the scope of the use code must not extend beyond the scope of the patent claims(s) and, within the boundary established by the patent claim(s), the use code must only describe patented method of use that has been approved by FDA as reflected in approved product labeling. the use code must contain adequate information to assist 505(b)(2) application and abbreviated new drug applications (ANDA) applicants in determining whether a listed method-of-use patent claims a use for which the 505(b)(2) application or ANDA applicant is not seeking approval (see 21 CFR 314.53(c)(2)(ii)(P)(3)). If you intend to use an existing use code that satisfies the current requirements of the statute and regulations, submit the existing use code for listing in the Orange Book. Use a maximum of 250 characters for each use code, and follow the general principles described below.

  • Patent method of use is broader than an indication or other approved condition of use in the labeling: The use code must only describe a patented method of use that is described in FDA-approved product labeling. If the method of use claimed by the patent uses different terminology than the approved labeling and/or is broader than an indication or other approved condition of use, then the use code would need to be phrased more narrowly than the patent claim to only describe the specific patented method of use that is described in FDA-approved product labeling.
  • Patented method of use is co-extensive with an indication or other approved condition of use in the labeling: The use code must describe only the specific approved method of use claimed by the patent.
  • Patented method of use is narrow than an indication or other approved condition or use in the labeling: If the method of use claimed by the patent does not cover an indication or other approved condition of use in its entirety, then the NDA holder must describe only the specific approved method claimed by the patent for which a claim of patent infringement could reasonably be asserted if a person not licensed by the patent owner engaged in the manufacture, use, or sale of the drug product - not the broader indication or other approved condition of use that may include, but is broader than, the use claimed by the patent.

Why: Our concern with 4.2b is that it leaves the individual completing the listing form, who usually is a patent attorney, with no guidance in Form 3542 itself regarding the use code. But, looking at the instructions for filling out Form 3542 section 4.2b, they seem to be in harmony with the guiding principles of the case law. The revision includes information verbatim from the instructions.

Summary of Section 4

FDA will not list the patent in the Orange Book as claiming the method of use if:

  • the answer to question 4.1 or 4.2 is “No,” or
  • the answer to 4.2 is “Yes” and the information requested in 4.2a and 4.2b is not provided in full.

Rewrite Summary of Section 4 as:

FDA will not list the patent in the Orange Book as claiming the method of use if the answer to 4.1 is no. Even if the answer to section 4.1 is yes, FDA will not list the patent in the Orange Book if sections 4.2, 4.2a and 4.2b are not completed.