DETAILED ACTION
Claims 1-23, 25, 29, and 31-32, submitted 25 October 2024, are pending in the application and subject to examination in the instant Office 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 .
Specification
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Rejections - 35 USC § 112
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.
Claim 23 is 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 treatment of pancreatic cancer wherein the pancreatic cancer has RAS mutation selected from G12C, G12D, G12V, G12R, G13D and Q61H does not reasonably provide enablement for when the pancreatic cancer has a RAS mutation selected from G12R, G12A, G12S or G13C. 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.
Breadth of the Claims
Claim 23 recites the limitations “…wherein the RAS mutation is a mutation selected from the group consisting of G12C, G12D, G12V, G12R, G12A, G12S, G13C, G13D, and Q61H.”. The instant specification does not provide support for all of the listed RAS mutations.
Nature of the Invention
The nature of the invention is within the pharmaceutical arts with regards to treating pancreatic cancer by administering 10 mg to 500 mg of Compound A.
State of the Prior Art
The state of the prior art is what one skilled in the art would have known, at the
time the application was filed, about the subject matter to which the claimed invention
pertains. The relative skill of those in the art refers to the skill of those in the art at the
time the application was filed. See MPEP 2164.05(b). See Pac. Bioscience of Cal., Inc.
v. Oxford Nanopore Techs., Inc., 996 F.3d 1342, 1352, 2021 USPQ2d 519 (Fed. Cir.
2021).
The state of the prior art provides evidence for the degree of predictability in the
art and is related to the amount of direction or guidance needed in the specification as
filed to meet the enablement requirement. The state of the prior art is also related to the
need for working examples in the specification. See MPEP 2165.05(a).
Koltun et al, ("Direct targeting of KRASG12X mutant cancers with RMC-6236, a first-in-class, RAS-selective, orally bioavailable, tri-complex RASMULTI (ON) inhibitor." Cancer research 82.12_Supplement (2022): 3597-3597.) discloses the use of the compound RMC-6236, the designated name of Compound A of the claimed invention, in the treatment of cancers with RAS mutations. For example, Koltun states “RMC-6236 at tolerable doses induced profound and durable tumor regressions in multiple cell line-derived (CDX) and patient-derived (PDX) RASMUT xenograft models, including NSCLC, CRC and PDAC.” (Abstract). This reference also specifies that RMC-6236 has anti-tumor activity in KRAS position 12 mutant tumors by teaching “Anti-tumor activity was particularly notable in KRAS position 12 (G12X) mutant tumors, particularly KRASG12D, KRASG12V, and KRASG12R, with significant tumor regressions observed.” (Abstract).
Punekar et al. ("The current state of the art and future trends in RAS-targeted cancer therapies." Nature reviews Clinical oncology 19.10 (2022): 637-655.) teaches the current state of the art in RAS-targeted cancer treatment. With regards to the treatment of RAS mutated cancer with RMC-6236, Punekar states “This agent is a RASMULTI- on inhibitor that forms tri- complexes with cyclophilin A and several KRAS mutants, with activity against KRASG12D, KRASG12V and KRASG12R mutations demonstrated in preclinical models.” (pg. 650, Section “Extending the breadth of RAS inhibitors”, Subsection “KRAS-on inhibitors”, Left Col., 2nd paragraph).
If a publication demonstrates that those of ordinary skill in the art would find that a particular invention was not enabled years after the filing date, the publication would be evidence that the claimed invention was not possible at the time of filing. See In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513-14 (Fed. Cir. 1993). See MPEP 2164.05(a). In view of the MPEP, it is appropriate to use post filed art as evidence to limit the scope of the instantly claimed invention based on what is known in the art and in the absence of disclosed data teaching otherwise. Cregg et al. ("Discovery of daraxonrasib (RMC-6236), a potent and orally bioavailable RAS (ON) multi-selective, noncovalent tri-complex inhibitor for the treatment of patients with multiple RAS-addicted cancers." Journal of Medicinal Chemistry 68.6 (2025): 6064-6083.) teaches that RMC-6236 had “the greatest potency for G12C (IC50 = 35 nM) and the least potency for G12D (IC50 = 229 nM)” followed by “Daraxonrasib (RMC-6236) potently reduced cellular phospho ERK (pERK), a marker of RAS activation, and cellular proliferation in eight cell lines representing a range of RAS variants including wild-type KRAS and G12V, G12C, G12D, G12R, G13D, Q61H, and NRAS Q61R” (pg. 6075, Section “Results and Discussion”, Right Col., 3rd paragraph). The post filing art supports the notion that unpredictability persists with regards to the treatment of pancreatic cancer with a RAS mutation wherein the RAS mutation is selected from G12R, G12A, G12S or G13C.
Level of Skill in the Art
The person of ordinary skill in the art is a person who is presumed to have known
the relevant art at the relevant time. Factors that may be considered in determining the
level of ordinary skill in the art may include: (A) “type of problems encountered in the art;” (B) “prior art solutions to those problems;” (C) “rapidity with which innovations are made;” (D) “sophistication of the technology; and” I “educational level of active workers in the field. In a given case, every factor may not be present, and one or more factors may predominate.” In re GPAC, 57 F.3d 1573, 1579, 35 USPQ2d 1116, 1121 (Fed. Cir. 1995); Custom Accessories, Inc. v. Jeffrey-Allan Indus., Inc., 807 F.2d 955, 962, 1 USPQ2d 1196, 1201 (Fed. Cir. 1986); Environmental Designs, Ltd. V. Union Oil Co., 713 F.2d 693, 696, 218 USPQ 865, 868 (Fed. Cir. 1983). See MPEP 2141.03 (I).
The invention described pertains to the medical or pharmaceutical arts. One of
ordinary skill would be trained in pharmacology, biochemistry, medicine, or a related art
with a Ph. D or other advanced degree in these or other related fields.
Level of Predictability in the Art
The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability of the art. In re Fisher, 427, F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The “amount of guidance or direction” refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art in unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. The scope of the required enablement varies inversely with the degree of predictability involved, but even in unpredictable art, a disclosure of every operable species is not required. A single embodiment may provide broad enablement in cases involving predictable factors, such as mechanical or electrical elements. In re Vickers, 141 F.2d 522, 526-27, 61 USPQ 122, 127 (CCPA 1944); In re Cook, 439 F.2d 730, 734, 169 USPQ 298, 301 (CCPA 1971). However, in applications directed to inventions in arts where the results are unpredictable, the disclosure of a single species usually does not provide an adequate basis to support generic claims. In re Soll, 97 F.2d 623, 624, 38 USPQ 189, 191 (CCPA 1938). In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). See MPEP 2164.03. The applicant would need to provide more objective evidence to support the enablement of the aforementioned claims to contrast the unpredictability of the subject matter art.
There is unpredictability in the field of endeavor regarding the currently claimed method of treating pancreatic cancer containing a RAS mutation selected from those listed in instant claim 23. The unpredictability is based on the fact that there is currently no art available that teaches or suggest that the compound, RMC-6236, is capable of treating pancreatic cancer containing RAS mutations selected from G12R, G12A, G12S or G13C. Moreover, unpredictability stems from the instant specification not teaching the treatment of a cancer containing the aforementioned RAS mutations.
Amount of Direction Provided by the Inventor
The amount of direction provided by the inventor is correlated by the nature of the unpredictability of the art. Given the context and scope of the claims mentioned above, the inventor failed to provide the necessary amount of direction for one skilled in the art to adequately use the invention across all suggested utility in the broadly stated disease and disorders disclosed above. (See: Section (A) Breadth of the Claims).
The Applicant has disclosed guidance for certain aspects of the invention such as the study design for Compound A, RMC-6236, in subjects with solid tumors that contain KRAS mutations, as found in Example 1. Example 2 teaches the treatment-related adverse effects of administering Compound A in doses ranging from 10 to 400 mg. Regarding the treatment of pancreatic cancers with KRAS mutations, Example 4 teaches the treatment of a patient with KRASG12D pancreatic ductal adenocarcinoma (PDAC) with 80 mg of Compound A. Example 7 teaches the treatment of a patient with KRASG12R PDAC with 160 mg of Compound A. Example 8 teaches the combination treatment of mice bearing human KRASG12C non-small cell lung cancer xenograft tumors with Compound A and RMC-6291.
Existence of Working Examples
The provided working examples focused on the treatment of PDAC and NSCLC containing RAS mutations at the 12 positions. Specifically, the examples detailed cancers containing KRASG12D, KRASG12R and KRASG12C mutations. The prior and post filed art was relied upon to support the claim limitation wherein the mutation is selected from G12V, G13D and Q61H, detailed above. The specification and field of art do not, however, support the notion that Compound A is capable of treating pancreatic cancer containing all of the listed mutations. Thus, one skilled in the art would be unable to adequately use the invention without unduly experimentation, which would require the practitioner to discover that which the Applicant has failed to disclose.
Quantity of Experimentation Needed to Make or Use the Invention Based on the Content of the Disclosure
As previously stated, the amount of experimentation depends on the art, the predictability of the art, and the direction provided by the inventor. For one skilled in the art to practice the invention as disclosed, the applicant would be required, but not limited to providing:
Experimentation to show treatment of a pancreatic cancer containing a RAS mutation for all of the listed mutations of instant claim 23.
Claim Rejections - 35 USC § 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.
Claims 1-23, 25, 29, and 31-32 are rejected under 35 U.S.C. 102(a)(2) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Aay et al. (US 2022/0105185 A1).
Claim 1 is rejected on the basis that Aay teaches a method of treating pancreatic cancer in a human subject in need thereof (paragraph 0391; paragraph 0347), the method comprising administering a dose ranging from about 5 mg to about 500 mg (paragraph 0367) of Compound A122, shown below.
Compound A122
PNG
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257
387
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Greyscale
(pg. 75, Table 1a, Second compound)
Claims 2-15 are rejected on the basis that Aay teaches administering a dose of the compound ranging from about 5 mg to about 500 mg per day which encompasses the limitations of the aforementioned dependent claims (paragraph 0367). Claim 2 is drawn to the administration of Compound A at a range of 120 mg to 500 mg. Claim 3 is drawn to the administration of Compound A at a range of 160 mg to 500 mg. Claim 4 is drawn to the administration of Compound A at a range of 250 mg to 500 mg. Claim 5 is drawn to the administration of Compound A at a range of 300 mg to 500 mg. Claim 6 is drawn to the administration of Compound A at a range of 400 mg to 500 mg. Claim 7 is drawn to the administration of Compound A at a dose of 120 mg. Claim 8 is drawn to the administration of Compound A at a dose of 160 mg. Claim 9 is drawn to the administration of Compound A at a dose of 200 mg. Claim 10 is drawn to the administration of Compound A at a dose of 250 mg. Claim 11 is drawn to the administration of Compound A at a dose of 300 mg. Claim 12 is drawn to the administration of Compound A at a dose of 350 mg. Claim 13 is drawn to the administration of Compound A at a dose of 400 mg. Claim 14 is drawn to the administration of Compound A at a dose of 450 mg. Claim 15 is drawn to the administration of Compound A at a dose of 500 mg. These ranges and doses are encompassed by the range taught by Aay; thus, it would have been prima facie obvious for one skilled in the art to administer the compound of the instant invention at any dose within the range of 5 mg to 500 mg.
Claim 16 is rejected as Aay teaches that the compound of the invention is administered in a single dose or divided doses (paragraph 0367).
Claim 17 is rejected as Aay teaches daily administration of the compounds of the invention for a period of 28 days (paragraph 1508). Therefore, it would have been prima facie obvious for one skilled in the art to administer Compound A 1-7 times a week as the reference teaches continuous daily administration for 4 weeks.
Claim 18 is rejected in part as Aay teaches the administration of the drug can be administered for one day to one year (paragraph 0370). Thus, it would have been prima facie obvious for one skilled in the art, in view of the teachings of Aay, to administer Compound A for up to at least 12 months.
Regarding claims 21-23, Aay teaches that in some embodiments, the cancer comprises a Ras mutation (paragraph 0326). Additionally, this reference teaches wherein the Ras mutation is at position 12, 13, or 61 (paragraph 0883), which reads on the limitations of instant claim 22. Claim 23 is rejected on the basis that Aay teaches that the mutation is selected from G12C, G13C, G12A, G12D, G13D, G12S, G12V, G12R or Q61H (paragraphs 0386 and 0388).
Claim 25 is rejected on the basis that Aay teaches wherein the cancer is pancreatic cancer and further wherein the pancreatic cancer is pancreatic ductal adenocarcinoma (paragraph 0376).
With respect to claim 29, Aay teaches wherein the method further comprises administering an additional anticancer therapy (paragraph 0898).
Regarding claim 31, Aay does not teach wherein the subject has received at least one prior cancer therapy. However, it would have been prima facie obvious for one skilled in the art to at least try to administer the compound of the instantly claimed invention in the treatment of cancer to a subject who has received prior treatment in an effort to discover a better treatment.
Claim 32 is rejected on the basis that, while Aay does not teach wherein the subject has locally advanced or metastatic PDAC, it would have been prima facie obvious for one skilled in the art to try to treat a subject with locally advanced or metastatic PDAC through routine experimentation. Additionally, the Examiner notes that Applicant’s specification contains no data regarding treatment of metastatic or advanced PDAC, therefore, the Examiner infers that Applicant’s asserted treatment of metastatic or advanced PDAC is not evidence of unexpected or surprising results.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 1-16, 21-23, and 29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-19 and 21 of copending Application No. 19/219,571 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1-19 and 21 of ‘571 either anticipate or are identical to that of the claims of the instant application. Independent claim 1 of ‘571 claims an identical Compound A for the treatment of a cancer in a human subject in need thereof. While the aforementioned claim is drawn the treatment of a lung cancer, the Examiner notes that the invention as defined in the specification of ‘571 recites “76-year-old man diagnosed with stage II PDAC in 2017 and with metastatic disease to the lung in 2022. The patient had received 4 prior therapies; surgery; gemcitabine/nab-paclitaxel (neoadjuvant); Gemcitabine/capecitabine (adjuvant); and gemcitabine/nab-paclitaxel/TTX-030 (anti CD39 monoclonal antibody). The patient started with 80 mg QD of Compound A. Baseline ctDNA was not detectable. At cycle 5 the patient had a confirmed partial response”, found on page 98 of the specification in Example 4. Consequently, it is proper to look at the disclosed utility in the reference disclosure to determine the overall question of obviousness in a nonstatutory double patenting context. See Sun Pharm. Indus., Ltd. v. Eli Lilly & Co., 611 F.3d 1381, 95 USPQ2d 1797 (Fed. Cir. 2010). As such, the disclosure of ‘571 teaches an identical utility, thus obviating that of the instant application which necessitates the instant rejection.
Claim 1 of ‘571 obviates instant claim 1 because, while the cancers being treated are different, the compound of the invention is identical to Compound A of the instant application and includes the claimed range of the total daily dose.
Claims 2-16 are also anticipated by claims 2-16 of ‘571 because the ranges and doses administered are identical to that recited in the cited claims of the instant application.
Claims 21-23 are anticipated by claims 17-19 of ‘571 because they both claim wherein the cancer comprises a RAS mutation, wherein the RAS mutation is at position 12, 13 or 61, and are drawn to the same list of mutations (e.g., G12C, G12D, G12V, G12R, G12A, G12S, G13C, G13D or Q61H).
Claim 29 is anticipated by claim 21 of ‘571 because the claims recited are identical in that the limitations recites wherein the method further comprises administering an additional anticancer therapy.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JUSTIN CHRISTOPHER SANCHEZ whose telephone number is (703)756-5336. The examiner can normally be reached Monday -Friday (0730-1700).
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JUSTIN CHRISTOPHER SANCHEZ
Examiner
Art Unit 1622
/J.C.S./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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