DETAILED ACTION
Notice of AIA Status
The instant application, filed on or after 16 March 2013, is being examined under the first inventor to file provisions of the Leahy-Smith America Invents Act (AIA ).
Benefit of Earlier Filing Date
The instant application was filed 14 August 2023; is a national stage application of PCT/US2022/016441, filed 15 February 2022, and claims the benefit of U.S. Prov. Pat. App. Serial No. 63/149,635, filed 15 February 2021. Acknowledgment is made of Applicant’s claim.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 14 November 2023; 21 November 2023; and 22 January 2024 are acknowledged and have been considered.
Status of the Claims
The listing of claims filed 5 April 2024 has been examined.
Claims 1–40 are pending. Claims 3, 4, 6, 8–15, and 17–40 are amended.
Claim Objections
Claims 34–38 are objected to for minor informalities.
Claim 34 recites “USP1.” Claims 35 and 36 recite “BRCA1” and “BRCA2.” Claim 37 recites “ATM.” Claim 38 recites “PARP.”
To avoid confusion, acronyms should be defined in the claims, at least in the first instance (e.g., replace “PARP” with “poly(ADP-ribose) polymerase (PARP)”).
Appropriate correction is required.
Claim Rejections - 35 U.S.C. § 112
The following is a quotation of 35 U.S.C. § 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
(i) Claims 1–40 are rejected under 35 U.S.C. § 112(a) as failing to comply with the written description requirement. The claims contain subject matter (i.e., prodrugs) that was not described in the Specification in such a way as to reasonably convey to one of ordinary skill in the art that Applicant, at the time the application was filed, had possession of the claimed invention.
In Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc), the Federal Circuit stated “the hallmark of written description is disclosure.” A specification adequately describes an invention when it “reasonably conveys to those skilled in the art the inventor had possession of the claimed subject matter as of the filing date.” (Id.). “A ‘mere wish or plan’ for obtaining the claimed invention is not adequate written description.” Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1348 (Fed. Cir. 2011).
What is required to meet the written description requirement “varies with the nature and scope of the invention at issue, and with the scientific and technologic knowledge already in existence.” Capon v. Eshhar, 418 F.3d 1349, 1357 (Fed. Cir. 2005). In Ariad, the Federal Circuit explained what is required to meet the written description requirement:
This inquiry, as we have long held, is a question of fact. Ralston Purina, 772 F.2d at 575. Thus, we have recognized that determining whether a patent complies with the written description requirement will necessarily vary depending on the context. Capon v. Eshhar, 418 F.3d 1349, 1357–58 (Fed. Cir. 2005). Specifically, the level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology. Id. For generic claims, we have set forth a number of factors for evaluating the adequacy of the disclosure, including “the existing knowledge in the particular field, the extent and content of the prior art, the maturity of the science or technology, [and] the predictability of the aspect at issue.” Id. at 1359.
(Ariad, at 1351).
The written description of a genus, such as a chemical genus, “requires a precise structure, formula, [or] chemical name” of the claimed subject matter sufficient to distinguish it from other materials. Regents of the Univ. of Cal. v. Eli Lilly & Co., 199 F.3d 1559, 1568 (Fed. Cir. 1997). The Federal Circuit commented on that case in the Ariad decision:
We held that a sufficient description of a genus instead requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can “visualize or recognize” the members of the genus. Id. at 1568-69. We explained that an adequate written description requires a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials. Id. at 1568 (quoting Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993)). We have also held that functional claim language can meet the written description requirement when the art has established a correlation between structure and function. See Enzo, 323 F.3d at 964 (quoting 66 Fed. Reg. 1099 (Jan. 5, 2001)). But merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing that one has invented a genus and not just a species.
(Ariad, at 1350).
The factors outlined in the above Federal Circuit cases are analyzed with respect to the claimed invention in turn below.
(A) The nature and scope of the claim invention in view of the specification: relates generally to the chemical art and more specifically to the pharmaceutical art; and even more specifically to a compound of Formula (I), including a salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof; a pharmaceutical composition comprising the compound; and methods of administering the compound to a patient to treat cancer.
A salt, hydrate, solvate, stereoisomer, or tautomer of a compound of Formula (I) would be represented by essentially the same chemical structure as the base compound; however, a prodrug requires a modification to the structure of the compound of Formula (I) and the modification may involve the addition of atoms or functional groups to the chemical structure via covalent bonding.
The Specification does not provide any guidance or examples for preparing a prodrug of a compound of Formula (I). Such guidance may include, for example, the identification of which atoms on the core structure would be targeted for modification, what the prodrug moiety would be, and how the prodrug compound would be prepared from the compound of Formula (I).
(B) The extent and content of the prior art: The compounds of Formula (I) appear to be free of the prior art. Prodrugs are known in the prior art. Considered as a whole, while the prior art may provide guidance as to which prodrugs may be useful, the prior art does not inform one of ordinary skill in the art how a compound of Formula (I) should be modified or how to make and use a prodrug of such compounds. Accordingly, Applicant’s disclosure is critical to show possession.
(C) The maturity of the science or technology: While prodrugs have existed for decades, the claims are specifically directed to a prodrug of a compound of Formula (I). When considered as a whole, the science relevant to making and using prodrugs of the compound of Formula (I) is in its infancy because the compounds appear to be novel.
(D) The predictability of the aspect at issue: the chemical and pharmaceutical arts are generally recognized as unpredictable. In re Fisher, 427 F.2d 833, 839 (CCPA 1970). The art requires, for example, each potential drug candidate to be assessed for physiological activity. (Id.). Applications in unpredictable arts require more specific disclosures to satisfy the statutory requirement. In this case, there is no evidence suggesting the claimed invention is more predictable than the chemical and pharmaceutical arts are generally.
The question of written description
After considering the above factors and evidence discussed therein, Examiner finds the specification does not adequately describe a representative number of prodrug species for a compound of Formula (I), or provide sufficient guidance for making such a prodrug. As such, the specification does not reasonably convey to those skilled in the art that applicant had possession of the claimed subject matter as of the filing date.
Examiner recommends deleting “prodrug” from the claims.
(ii) Claims 32–40 are rejected under 35 U.S.C. § 112(a) because the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with the claims.
MPEP § 2164.01(a) explains how enablement for the claimed invention can be analyzed:
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is “reasonable” or is “undue.” . . . These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The Wands factors are analyzed with respect to the claimed invention in turn below.
The breadth of the claim is broad in scope, as it extends to treating any species of cancer with a compound of Formula (I), which encompasses thousands of different compounds.
The nature of the invention generally relates to the pharmaceutical art and more specifically to a method of treating cancer with a compound of Formula (I) or a pharmaceutical composition thereof. Thus, the nature of the invention is sophisticated.
The state of the prior art is in its infancy. Generally, in order to treat a disease, one of skill in the art must identify a biological target for affecting the disease, demonstrate a first drug candidate some way modulates the normal processes of the biological target, and demonstrate that a subject would benefit from such modulation without detrimental side effects. Typically, the process includes in vitro laboratory screening, in vivo testing, and clinical testing. Once that process has been successfully completed by the first drug candidate, subsequent drug candidates can benefit from the established proof of concept if a substantial correlation can be established between the first drug candidate and the subsequent drug candidates.
In this case, a recent review article explains that only two ubiquitin inhibitors have entered clinical trials for the treatment of cancer. (Dewson et al., Nature Reviews Cancer (2023), 23, 842–862, at 857, Box3 (“Dewson”)). For example, KSQ-4279 was proven to be specific for USP1 and is in clinical studies as a single agent and in combination with a PARP inhibitor. (Id.). Dewson explains, “Numerous deubiquitinating enzyme (DUB) inhibitors have been described; however, to date, few have achieved sufficient specificity to enable meaningful association of a DUB to a particular signaling context.” (Id.).
The level of one of ordinary skill may be found by inquiring into: (i) the type of problems encountered in the art; (ii) prior art solutions to those problems; (iii) the rapidity with which innovations are made; (iv) the sophistication of the technology; and (v) the education level of active workers in the field. Custom Accessories, Inc. v. Jeffrey-Allan Industries, Inc., 807 F.2d 855, 962 (Fed. Cir. 1986). All of the factors may not be present in every case, and one or more of them may predominate. Envtl. Designs, Ltd. v. Union Oil Co., 713 F.2d 693, 696 (Fed. Cir. 1983). Based on the typically high education level of workers in the pharmaceutical art and the high degree of sophistication required to solve problems encountered in the art, Examiner finds a person having ordinary skill in the art would have at least a college degree in chemistry, biology, biochemistry, pharmacology, or a related field, and several years of experience.
The level of predictability in the art is generally unpredictable. The relevant art requires each potential drug candidate to be assessed for physiological activity. In re Fisher, 427 F.2d 833, 166 USPQ 18, 24 (CCPA 1970). The more unpredictable an area is the more specific disclosure is necessary to satisfy the statutory requirement. MPEP § 2164.02(II) explains that a correlation between the claimed invention and the evidence provided in an application, along with a correlation between the evidence and the models recognized in the art, are required:
“Correlation” as used herein refers to the relationship between in vitro or in vivo animal model assays and a disclosed or a claimed method of use. An in vitro or in vivo animal model example in the specification, in effect, constitutes a “working example” if that example “correlates” with a disclosed or claimed method invention. If there is no correlation, then the examples do not constitute “working examples.” In this regard, the issue of “correlation” is also dependent on the state of the prior art. In other words, if the art is such that a particular model is recognized as correlating to a specific condition, then it should be accepted as correlating unless the examiner has evidence that the model does not correlate. Even with such evidence, the examiner must weigh the evidence for and against correlation and decide whether one skilled in the art would accept the model as reasonably correlating to the condition. In re Brana, 51 F.3d 1560, 1566, 34 USPQ2d 1436, 1441 (Fed. Cir. 1995) (reversing a USPTO decision based on finding that in vitro data did not support in vivo applications).
Further, treatments may be effective for some subjects and ineffective for other subjects. Thus, each candidate for pharmaceutical or veterinary medicine must be evaluated on its own even when a nexus to an existing drug or class of drugs has been established.
The amount of direction provided by the inventor is limited to evaluating the relative in vitro activity of certain compounds against USP1-UAF1, in a viability assay for non-isogenic pair BRCA1 mutant and BRCA1 WT, and in an AlphaLISA assay. (Spec., Table 1).
The existence of working examples relate to in vitro activity and viability assays. (Spec., Examples 135, 136). There are no examples demonstrating in vivo activity against a specific type of cancer with a compound of Formula (I).
The quantity of experimentation needed to make or use the invention based on the content of the disclosure is extensive, as it includes in vitro and in vivo screening for each species of cancer encompassed by the claims.
Scope of Enablement Conclusion
In view of the Wands factors discussed above, the disclosure of the instant application does not reasonably enable a person having ordinary skill in the art to use the full scope of the claimed invention. The breadth of the claims is broad in scope; the nature of the invention is sophisticated; the state of the prior art is in its infancy; the level of skill in the art is high; the pharmaceutical art is unpredictable; the direction provided by the inventor is limited to evaluating the relative in vitro activity of certain compounds; there are no working examples demonstrating in vivo activity against a specific cancer; and the quantify of experimentation needed to practice the claimed invention is extensive. Thus, when the evidence is considered as a whole, undue experimentation would be required to practice the full scope of the claimed invention.
Allowable Subject Matter
The claims are rejected because the specification lacks adequate written description for a prodrug of a compound of Formula (I); however, the compounds of Formula (I) are free of the prior art. The closest prior art reference is US 2009/0149458 (“Chen”). Chen discloses compounds according to Formula (I):
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194
252
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, including numerous subgenera and species. (Chen, ¶¶15, 52–127, 232–291). The following compounds were indexed in CAS Registry database for Chen:
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330
545
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330
513
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The indexed compounds correspond to instant Formula (I) when: X1 = N; X2 = CRXc2; RXc2 = H; R2 = H; R6 = heterocycle; Ring B = substituted aryl [phenyl]; L = CRcRc’; Rc = H; Rc’ = H; Ring A = heterocycle; and R1 = heteroaryl; however as claimed R6 cannot be heterocycle.
Communication
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jason Nolan at (571) 272-2480. The examiner can normally be reached Monday through Friday between 9:00–5:00.
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/JASON M. NOLAN/Patent Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623