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 .
DETAILED ACTION
Applicant’s election without traverse of 1) Formula 1a (compound DN200434) as a species of Formula A, 2) osimertinib as a species if tyrosine kinase inhibitors, and 3) lung cancer as a cancer type in the reply filed on 06/17/2026 is acknowledged.
Claims 1-23 are pending.
Claims 1-23 are under examination on the merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Claims 1-23 have an effective filing date of 06/02/2022, corresponding to PRO 63/348,185.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 06/01/2023, 10/13/2023, and 04/30/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
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.
Claims 3 and 7-23 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 the species of claims 4, 10, and 18, does not reasonably provide enablement for each and every possible variation of Formula A, where L, R1, Ar, and R2 form a wide range of compounds. 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/or use the invention commensurate in scope with these claims.
In evaluating the enablement question, several factors are to be considered. In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988); Ex parte Forman, 230 USPQ 546. The factors include: 1) The nature of the invention, 2) the state of the prior art, 3) the predictability or lack thereof in the art, 4) the amount of direction or guidance present, 5) the presence or absence of working examples, 6) the breadth of the claims, and 7) the quantity of experimentation needed.
HOW TO MAKE: The nature of the invention in the instant case, has claims which recite compounds of Formula A, where L, R1, Ar, and R2 form a wide range of compounds. The magnitude of possible compounds are not described in the disclosure in such a way that one of ordinary skill in the art would know how to prepare the various compounds suggested by claims 3, 9, and 17. For example, accounting for the numerous options for each R side chain, there are thousands of possible variations encompassed in instant claims 3, 9, and 17. Furthermore each L (linker) moiety encompasses numerous molecules. Thus when combining the thousands of variants of the compound of Formula A across the numerous variants of each of L, the total number of embodiments encompassed by the conjugate of the claims extends into the millions. In view of the lack of direction provided in the specification regarding starting materials, the lack of working examples, and the general unpredictability of chemical reactions, it would take an undue amount of experimentation for one skilled in the art to make the claimed compounds, across the enormous scope of the claims, and therefore practice the invention.
HOW TO USE: Claim 7 is drawn to a method of preventing or inhibiting tyrosine kinase resistance of a subject with any type of cancer or enhancing a treatment of tyrosine kinase inhibitor-resistant cancer of any type in a patient. Any evidence presented must be commensurate in scope with the claims and must clearly demonstrate the effectiveness of the claimed compounds. 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 these claims. For example, the specification describes no means by which the claimed compounds may be used to prevent or inhibit tyrosine kinase resistance of a subject with any type of cancer or enhancing a treatment of tyrosine kinase inhibitor-resistant cancer of any type in a patient. Claim 13 is drawn to a method of treating any type of cancer in need of a subject. Any evidence presented must be commensurate in scope with the claims and must clearly demonstrate the effectiveness of the claimed compounds. 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 these claims. For example, the specification describes no means by which the claimed compounds may be used to treat any type of cancer.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Liebel-Flarsheim Co. v. Medrad, Inc. 481 F.3d 1371, 82 USPQ2d 1113; Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008).
Breadth of claims and nature of invention:
The claimed subject matter pertains to methods of 1) preventing or inhibiting tyrosine kinase resistance of a subject with any type of cancer, 2) enhancing a treatment of tyrosine kinase inhibitor-resistant cancer of any type in a patient, and 3) treating any type of cancer. Examples 2 and 3 of the specification details the treatment of treating liver cancer, and Example 4 of the specification details the treatment of treating lung cancer. Example 5 demonstrates an anti-cancer effect of the claimed invention in lung, pancreas, liver, and ovarian cancer cell lines.
State of the art and level of ordinary skill:
At the time of the effective filing date, the level of skill to treat cancer, including preventing/inhibiting tyrosine kinase resistance of a subject with cancer or enhancing a treatment of tyrosine kinase inhibitor-resistant cancer, was high, requiring advanced knowledge of medicine and cell biology, typically requiring a doctoral degree and several years of experience. One of skill in the art is well-aware that cancer is difficult to prevent and treat, and there are numerous molecular mechanisms which may drive cells to become cancerous, from generic abnormalities to environmental factors. The variety of molecular mechanisms for cancer require highly personalized treatment for each type of cancer, depending on the patient; however, the instant disclosure does not provide sufficient in vitro or in vivo evidence showing that the instantly claimed methods may be used to 1) prevent or inhibit tyrosine kinase resistance of a subject with any type of cancer, 2) enhance a treatment of tyrosine kinase inhibitor-resistant cancer of any type in a patient, and 3) treat any type of cancer.
The level of predictability of the art:
Pharmaceutical therapies in the absence of in vivo clinical data are unpredictable for the following reasons: (1) the protein may be inactivated before producing an effect, i.e. such as proteolytic degradation, immunological inactivation or due to an inherently short half-life of the protein; (2) the protein may not reach the target area because, i.e. the protein may not be able to cross the mucosa or the protein may be adsorbed by fluids, cells and tissues where the protein has no effect; and (3) other functional properties, known or unknown, may make the protein unsuitable for in vivo therapeutic use, i.e. such as adverse side effects prohibitive to the use of such treatment. See page 1338, footnote 7 of Ex parte Aggarwal, 23 USPQ2d 1334 (PTO Bd. Pat App. & Inter. 1992).
The amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention based on the content of the disclosure:
The specifications describes four compounds (Formulas 1a, 1b, 1c, and 1d) that meet the limitations of Formula A, as recited in claims 3, 9, and 17. Furthermore at p. 12, the specification states that “[i]n certain embodiments, the ERRy inverse agonist may be (E)-5-(4-hydroxyphenyl)- 5-(4-(4-isopropylpiperazin-1-yl)phenyl)-4-phenylpent-4-en-1-ol of Formula la (DN434 or DN200434), or a pharmaceutically acceptable salt thereof or an isomer thereof, or a solvate thereof.” The specification does not adequately teach how to effectively formulate the compound of Formula A across the claimed array of different L, R1, Ar, and R2 groups. The specification also fails to provide evidence showing that the instantly claimed methods may be used to 1) prevent or inhibit tyrosine kinase resistance of a subject with any type of cancer, 2) enhance a treatment of tyrosine kinase inhibitor-resistant cancer of any type in a patient, and 3) treat any type of cancer.
MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).”
In view of the lack of direction provided in the specification, the relatively few working examples, and the general unpredictability of chemical reaction, it would take an undue amount of experimentation for one skilled in the art to make the claimed compounds and practice the claimed methods. To be enabling, the specification of a patent must teach those skilled in the art how to make and use the scope of the claimed invention without undue experimentation.
As stated in the MPEP, 2164.08 “'[t]he Federal Circuit has repeatedly held that the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. ln re Wright, 999 F.2d 1557, 1561 27 USPQ2d 1510, 1513 (Fed. Cir. 1993). Nevertheless, not everything necessary to practice the invention need be disclosed. In fact, what is well known is best omitted. In re Buchner, 929 F.2d 660, 661, 18 USPQ2d 1331, 1332 (Fed. Cir. 1991). All that is necessary is that one skilled in the art be able to practice the claimed invention, given the level of knowledge and skill in the art. Further the scope of enablement must only bear a reasonable correlation to the scope of the claims. See, e.g., In re Fisher, 427 F.2d 833, 839,166 USPQ 18, 24 (CCPA 1970). As concerns the breadth of a claim relevant to enablement, the only relevant concern should be whether the scope of enablement provided to one skilled in the art by the disclosure is commensurate with the scope of protection sought by the claims. In re Moore, 439 F.2d 1232, 1236, 169 USPQ 236, 239 (CCPA 1971). See also Plant Genetic Sys., N.V. v. DeKalb Genetics Corp., 315 F.3d 1335, 1339, 65 USPQ2d 1452, 1455 (Fed. Cir. 2003) (alleged pioneer status of invention irrelevant to enablement determination.”
Regarding the recitation of “preventing tyrosine kinase resistance of a subject with cancer,” as recited in claim 7, due to the high level of unpredictability in the art, the skilled artisan would need significant guidance in preventing tyrosine kinase resistance of a subject with cancer by practicing the claimed method. The skilled artisan recognizes that preventing tyrosine kinase resistance indefinitely is an intractable proposition, if not now wholly impossible, given, for example, that numerous different tyrosine kinases have been identified, each having distinct chemical compositions and biological functions. Applicant is informed that this issue may be addressed by amending claim 7 to strike the recitation of “preventing.”
In conclusion upon careful consideration of the Wands factors that are used to determine whether undue experimentation is required to practice an invention, the amount of direction provided by the inventor and the working examples provided, as filed, is not deemed sufficient to enable the skilled artisan to make and/or use the invention commensurate in scope with the instant claims at the time the application was filed without undue experimentation. As claims 8, 10-12, 14-16, and 18-23 depend from claim 3, 7, 9, 13, or 17, yet fail to rectify the enablement issues, claims 8, 10-12, 14-16, and 18-23 are also rejected.
35 U.S.C. 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 2, 5-8, 11-16, and 19-23 are rejected under 35 U.S.C. 103 as being unpatentable over Kim et al. (Experimental and Molecular Medicine, 48: 1-7, 2016, in IDS from 06/01/2023), Jeong et al. (Mol Endocrinol, 26(8): 1443-1454, 2012), and Sorrentino et al. (US PG PUB 2019/0374545, publication date: 12/12/2019).
Kim et al. teach that “[o]rphan nuclear receptor estrogen-related receptor γ (ERRγ) regulates cell growth and tumorigenesis in various cancers. However, the clinical relevance of ERRγ to hepatocellular carcinoma (HCC) remains unclear. Here we examined the clinical significance of ERRγ in HCC and its potential as a therapeutic target. ERRγ levels in tissues from completely resected specimens from 190 HCC patients were examined immunohistochemically and their association with clinical stage and pathological grade was analyzed. Small interfering RNA (siRNA)-mediated knockdown of ERRγ (siRNA-ERRγ) or an ERRγ inverse agonist, GSK5182, were also used to examine the effects of ERRγ inhibition on the proliferation and growth of a human hepatoma cell line, PLC/PRF/5. Immunohistochemical analysis revealed that tumor tissues showed higher levels of ERRγ-positivity than adjacent non-tumor lesions. Tumors showing high levels of ERRγ immunoreactivity also had advanced tumor node metastasis (TNM) and Barcelona Clinic Liver Cancer stages and a higher Edmondson-Steiner grade. In addition, high-level expression of ERRγ in tumors of advanced TNM stage correlated with poorer overall survival. Treatment of PLC/PRF/5 cells with siRNA-ERRγ or GSK5182 inhibited proliferation through G1 arrest, increased expression of p21 and p27 and decreased expression of phosphorylated retinoblastoma protein. GSK5182-induced reactive oxygen species also suppressed the proliferation of PLC/PRF/5 cells. The present study showed that ERRγ expression is clinically significant in HCC; therefore, it can be considered a biomarker for HCC diagnosis. Moreover, the results provide a rationale for the use of ERRγ inhibitors such as GSK5182 as potential therapeutic agents.” See Abstract. Based upon the teachings of Kim et al., one of ordinary skill in the art would reason that an ERRγ inverse agonist, GSK5182, or siRNA-ERRγ may be used in the treatment of cancers that upregulate ERRγ, such as HCC.
Although Kim et al. teach a composition comprising a first composition comprising an agent capable of inhibiting estrogen-related receptor γ (ERRγ) protein activity or ERRγ gene expression, Kim et al. do not teach or suggest a combination comprising (a) a first composition comprising an agent capable of inhibiting estrogen-related receptor γ (ERRγ) protein activity or ERRγ gene expression, and (b) a second composition comprising a tyrosine kinase inhibitor. These deficiencies are remedied by Jeong et al. and Sorrentino et al.
Jeong et al. teach that “[l]ung cancer is the leading cause of cancer-related death. Despite a number of studies that have provided prognostic biomarkers for lung cancer, a paucity of reliable markers and therapeutic targets exist to diagnose and treat this aggressive disease. In this study we investigated the potential of nuclear receptors (NRs), many of which are well-established drug targets, as therapeutic markers in lung cancer. Using quantitative real-time PCR, we analyzed the expression of the 48 members of the NR superfamily in a human panel of 55 normal and lung cancer cell lines.” See Abstract. At Fig. 1, Jeong et al. demonstrate that in normal human bronchial epithelial cells (HBECs), ERRγ mRNA expression is low; however in non-small cell lung carcinoma (NSCLC) and small cell lung carcinoma (SCLC), the mRNA expression of ERRγ is increased relative to normal HBECs, demonstrating increased expression of ERRγ mRNA in various lung cancer cell lines.
At [0007], Sorrentino et al. teach that “[t]hird-generation irreversible pyrimidine EGFR-TKIs including osimertinib (TAGRISSO)… have emerged to target both EGFR-mutant and EGFR-mutant T790M-positive NSCLC… In phase I studies to date, treatment with either osimertinib or rociletinib has resulted in a response rate of >50% in EGFR-mutant EGFR-T790M NSCLC patients who have developed resistance to gefitinib or erlotinib…”
One of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to combine the teachings of Kim et al. with the teachings of Jeong et al. and Sorrentino et al. to develop a combination comprising (a) a first composition comprising an agent capable of inhibiting estrogen-related receptor γ (ERRγ) protein activity or ERRγ gene expression, and (b) a second composition comprising a tyrosine kinase inhibitor. One of ordinary skill in the art would have been motivated to do so, because Kim et al. teach a composition comprising a first composition comprising an agent capable of inhibiting ERRγ protein activity or ERRγ gene expression, specifically an ERRγ inverse agonist, GSK5182, or siRNA-ERRγ. As noted above based upon the teachings of Kim et al., one of ordinary skill in the art would reason that an ERRγ inverse agonist, GSK5182, or siRNA-ERRγ may be used in the treatment of cancers that upregulate ERRγ. Furthermore Jeong et al. demonstrate that in normal human bronchial epithelial cells (HBECs), ERRγ mRNA expression is low; however in NSCLC, the mRNA expression of ERRγ is increased relative to normal HBECs, demonstrating increased expression of ERRγ mRNA in various lung cancer cell lines. As such one of ordinary skill in the art would have been motivated to administer siRNA-ERRγ to NSCLC patients with tumor cells that demonstrate increased expression of ERRγ mRNA. Lastly one of ordinary skill in the art would have been motivated to modify the invention of Kim et al. and Jeong et al. to comprise the administration of osimertinib (TAGRISSO) to EGFR-mutant positive NSCLC patients, as taught by Sorrentino et al., because there would have been a reasonable expectation that the resultant invention would provide a therapeutic benefit to EGFR-mutant positive NSCLC patients with tumor cells that demonstrate increased expression of ERRγ mRNA. The invention of Kim et al., Jeong et al., and Sorrentino et al. meets the limitations of a combination comprising (a) a first composition comprising an agent capable of inhibiting estrogen-related receptor γ (ERRγ) protein activity or ERRγ gene expression, and (b) a second composition comprising a tyrosine kinase inhibitor. The invention of Kim et al., Jeong et al., and Sorrentino et al. meets the limitations of claims 1, 2, 5, 7, 8, 11, 13, 16, 19, 21, and 22.
With respect to claims 6, 12, and 20, the first composition in the claimed combination would necessarily have to be administered simultaneously with the second composition, separately, or sequentially.
With respect to claim 14, at [0006], Sorrentino et al. teach that “[u]nfortunately, while a reasonable number of patients with EGFR-mutant NSCLC respond to EGFR-TKI therapy initially, most patients who respond to therapy ultimately develop disease progression after about 9-14 months of treatment due to acquired resistance to the EGFR-TKI…”
With respect to claim 15, one of ordinary skill in the art would have been motivated to administer the invention of Kim et al., Jeong et al., and Sorrentino et al. to an NSCLC patient that has not previously undergone tyrosine kinase inhibitor treatment, because as a front-line therapy, there would have been a reasonable expectation that the invention of Kim et al., Jeong et al., and Sorrentino et al. would provide a therapeutic benefit to EGFR-mutant positive NSCLC patients with tumor cells that demonstrate increased expression of ERRγ mRNA.
With respect to claim 23, at [0009], Sorrentino et al. teach that resistance to EGFR-TKI (tyrosine kinase inhibitor) therapy can be addressed by administering said EGFR-TKI with the EGFR monoclonal antibody, cetuximab.
Therefore the invention as a whole was prima facie obvious to one of ordinary skill in the art, as evidenced by the references.
Allowable Subject Matter
Claim 4 is 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.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NELSON B MOSELEY II whose telephone number is (571)272-6221. The examiner can normally be reached on M-F, 9:00-6:00 EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis, can be reached at 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642
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