DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This application was filed on November 8, 2023 under 35 U.S.C. 111(a) and claims benefit to US Provisional Application No. 63/383,021, filed on November 9, 2022.
Information Disclosure Statement
The information disclosure statements (IDSs) filed on February 5, 2024, March 18, 2024, and June 12, 2024, have been acknowledged and considered.
Response to Election/Restrictions
Applicants’ election with traverse of Group I in the reply, filed on August 10, 2026, is acknowledged. The traversal is on the grounds that upon allowance of a generic claim, Applicants are entitled to rejoinder of any withdrawn process claims that are commensurate in scope with the allowable generic product claim, in accordance with MPEP §821.04. (Remarks, p.7). This argument is not persuasive because it does not point out any errors in the restriction requirement. Regardless, the Group I invention is allowable over the prior art. The restriction is therefore withdrawn and the Group II invention is rejoined.
Claims 1-20 are examined on the merits.
Claim Objections
Claim 13 is objected to because it recites “cancer/disease” in line 3 but recites only “cancer” in line 1. Thus, antecedent basis for “disease” is lacking. Appropriate correction is required.
Claims 18-20 are objected to for minor informalities. The claims recite “wherein the method of treating cancer is , . . ”; which implies a method separate from claim 14 (the claim from which claims 18-20 depend). To avoid issues due to a lack of clarity, for example, claim 18 can be amended to recite: “The method of claim 14 further comprising . . .” Claims 19 and 20 can be amended in a similar fashion. Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph 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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Claims 13, 14, and 17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating certain human cancers, like melanoma, it is not enabled for treating all human cancers as instantly claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these 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. The claim recites: “A method for treating cancer comprising administering to said patient a therapeutically effective amount of a compound of Formula (I) according to claim 1 pharmaceutically acceptable salt thereof wherein the cancer/disease is selected from: human cancers …” The claim therefore encompasses a method of treating all human cancers with a composition containing a therapeutically effective amount of a compound of Formula (I).
The nature of the invention generally relates to the pharmaceutical art and more specifically to a method of administering a compound of Formula (I) for treatment of human cancers. The instant specification states: “Data pooled from in vivo genetic screening using CRISPR-Cas9 genome editing to identify genes that cause resistance to checkpoint blockade identified that deletion of the protein tyrosine phosphatase (PTPN2) gene in tumor cells increased the efficacy of immunotherapy. The PTPN2 gene encodes a protein tyrosine phosphatase that regulates a range of intracellular processes. Loss of PTPN2 in tumor cells promotes amplified IFNy signaling, antigen presentation to T cells and growth arrest in response to cytokines; these data suggest that PTPN2 therapeutic inhibition may potentiate the effect of immunotherapies that invoke an IFNy response.” (Spec., p.2, ll. 4-12). Further stated is the inhibition of PTPN2 is a potential therapeutic strategy of cancer therapy regimens associated with immune checkpoint blockade (ICB) resistance (Spec., p.3, ll. 16-18). Thus, the nature of the invention is sophisticated.
The state of the prior art is discussed in a review article by Wang et al., European Journal of Medicinal Chemistry, 277 (2024), 116774 (“Wang”), which states: “While numerous past studies have validated the tumor-suppressing properties of PTPN2 in various human cancers, recent and in-depth research indicates that PTPN2 also exhibits some pro-cancer effects and is associated with a negative prognosis.” (Wang, p.5, Role of PTPN2 in cancer development). For instance, Wang teaches that PTPN2 was downregulated in liver cancer cells, based on this, inhibition of PTPN2 would further promote liver cancer like, hepatocellular carcinoma development (p. 6, Hepatic carcinoma). Wang also teaches that PTPN2 deficiency accelerates tumor formation in skin cancer and facilitates tumorigenesis in T-cell acute lymphoid leukemia cells (p. 6, Skin cancer & T-cell acute lymphoblastic leukemia).
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. Ent. 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 Brane, 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 includes background information as discussed in factor (A). The specification does not provide detailed guidance regarding treatment of all human cancers, including liver cancer and T-cell acute lymphoblastic leukemia.
The existence of working examples relates to methods of treating B16-F10 cells with a therapeutically effective amount of a compound of Formula (I), and biological assays, like the PhosphoSens kinase assay and the phosphatase activity assay, which uses DiFMUP as a fluorogenic substrate, to validate the compounds’ ability to inhibit PTPN2 (Spec., pp. 38-43). The present disclosure does not provide working examples for treating all human cancer cells, like skin cancer and T-cell acute lymphoblastic leukemia.
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 specific disease or disorder encompassed by the claims. As claimed, the indefinite scope of such diseases is essentially unbound.
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 teaches the tumor-suppressing properties of PTPN2; the level of skill in the art is high; the pharmaceutical art is unpredictable; the direction provided by the inventor is limited to treating B16-F10 skin cancer cells; and does not demonstrate possession of a method of treating all human cancers within the scope of, “A method for treating cancer comprising administering to said patient a therapeutically effective amount of a compound of Formula (I) according to claim 1 pharmaceutically acceptable salt thereof wherein the cancer/disease is selected from: human cancers…”; 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.
Examiner recommends amending the claim to omit “human cancers,” in claim 13 and specifying the cancers being treated in claims 14 and 17.
Claim 14 is rejected under 35 U.S.C. § 112(a) as failing to comply with the written description requirement. The claim contains subject matter 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.
Further, 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.
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: the claimed invention relates generally to the pharmaceutical art and more specifically to a method of treating cancer, where an example is a cell proliferation assay where B16-F10 melanoma cells are treated with the compounds of Formula (I). The claimed phrase “an additional therapeutic agent” encompasses genera having millions of distinct embodiments.
The Specification does not provide any working examples for the claimed invention. The Specification generally mentions the compounds of Formula I are administered in combination with an additional therapeutic agent wherein the additional therapeutic agent is an immunotherapeutic agent, radiation, surgery, chemotherapy, or administration of a biologic drug (Spec., p. 6, ll. 6-10; p. 24, ll. 20-24). The immunotherapeutic agent are antibodies like anti-PD-1, PD-L1, and CTLA-4; the biologic drug is a drug that stimulates the immune system by inhibiting DGKα and/or DGKζ, an antagonist of the PDI/PD-Ll axis and an antagonist of CTLA4 (Spec., p.24, ll. 26-30). The Specification does not provide any details related to a composition, a formulation, or a dose of an additional therapeutic agent. The Specification does not provide any details related to administering an additional therapeutic agent. The Specification does not provide any details related to testing the administration of compounds of Formula I and a second therapeutic agent for efficacy or synergy.
(B) The extent and content of the prior art: The compounds of Formula I are PTPN2 inhibitors (Spec., p. 3, ll. 22-31). According to clinical trials NCT04777994 and NCT04417465, two separate PTPN2 inhibitors, ABBV-CLS-484 and ABBV-CLS-579, respectively, were administered in combination with a PD-1 inhibitor (Arms and Interventions). Table 4 of Schichler et al., Front. Immunol. 14:1297175 (“Schichler”), shows the same clinical trials and also teaches inhibitors of DGKα and/or DGKζ have been used in combination with anti-PD-1 antibodies to show an additive effect in MC38 cells (Schichler, p. 7, 1st col.).
Accordingly, while the prior art does describe a combination therapy of PTPN2 and DGKα and/or DGKζ inhibitors with PD-1 inhibitors, the prior art does not describe examples of administering PTPN2 inhibitors with any additional therapeutic agents.
(C) The maturity of the science or technology: while combination drug therapies exist for administration of PTPN2 or DGKα and/or DGKζ inhibitors along with an additional therapeutic agent, like PD-1, there does not appear to be any pre-clinical or clinical trials that provide a proof of concept for the claimed invention to a method of administering compounds of Formula I and additional therapeutic agents broadly. As such, the science relevant to the claimed invention is in its infancy.
(D) The predictability of the aspect at issue: the pharmaceutical art is generally recognized as unpredictable. In re Fisher, 427 F.2d 833, 839 (CCPA 1970). The art requires each potential drug candidate to be assessed for physiological activity. Id. The more unpredictable an area is the more specific disclosure is necessary to satisfy the statutory requirement.
When the above factors and evidence discussed therein are considered as a whole, the specification (in view of the prior art) does not adequately describe a representative number of species to support the claimed genera of administering compounds of Formula I, and an additional therapeutic agent broadly. Accordingly, the Specification does not reasonably convey to those skilled in the art the Applicant had possession of the claimed subject matter as of the filing date.
Examiner recommends canceling claim 14 or amending the claim to incorporate the features of claim 15.
Allowable Subject Matter
Claims 15-16, 18, and 20 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claims 1-12 are allowable over the prior art. Close prior art is WO2019246513 (IDS submitted February 5, 2024, Foreign Patent Documents, Cite No. 1) (“Farney”) which teaches thiadiazolidine-1, 1,3-trione (TDZ) based compounds as PTP1/2 inhibitors (Abstract). Compound 266,
PNG
media_image1.png
101
210
media_image1.png
Greyscale
, is taught as a species that bears the TDZ moiety, substituted naphthalene group with a halogen, hydroxy, and pyridine. This species differs from the claimed invention, because it does not bear a benzimidazole moiety, in place of the naphthalene, nor does it have a methylene amino spacer in between the naphthalene and pyridine. Additionally, the attachment of the pyridine ring in Farney is meta to the nitrogen of the pyridine, while the claimed invention attaches ortho in the structure depicted in Formula (I). There is no teaching, suggestion, or motivation to make such changes in Farney. Therefore, the claimed subject matter is novel and nonobvious over the prior art.
Conclusion
Claims 13-14 and 17 are rejected.
Claims 15-16 and 18-20 are objected to. Claims 1-12 are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAHIL CHANDER AGGARWAL whose telephone number is (571)272-7755. The examiner can normally be reached 7am-5pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C Milligan can be reached at (571) 270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SAHIL CHANDER AGGARWAL/Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
