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 .
Response to Amendment
The amendments received 06/26/2026 have been entered. Claims 42-55 are pending. Claims 42-45 and 49-55 are examined herein. Claims 46-48 remain withdrawn. Any objection or rejection previously set forth in the Office Action mailed 12/29/2025 not maintained herein has been overcome and is withdrawn. The nonstatutory double patenting rejection over co-pending Application No. 17/789,293 has been withdrawn as the ‘293 application has been abandoned as of 06/26/2026.
Any new grounds for rejection set forth herein are necessitated by amendment.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 50-51 and 53-55 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 50 and 53 recite “the subject in need thereof”. This limitation lacks antecedent basis. Examiner suggests correcting to “a subject in need thereof”. Claims 51 and 54-55 are rejected for requiring the limitation at issue.
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 42-45 and 49-55 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 pancreatic cancer, non-small cell lung cancer, small cell lung cancer, and colorectal cancer, does not reasonably provide enablement for treating cancers . 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.
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).
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required: (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. Some experimentation is not fatal; the issue is whether the amount of experimentation is "undue"; see In re Vaeck, 20 USPQ2d 1438, 1444.
The treatment of cancer generally cannot possibly be considered enabled.
By way of background, four cases are of particular relevance to the question of enablement of a method of treating cancers broadly or even generally:
In In re Buting, 57 CCPA 777, 418 F.2d 540, 163 USPQ 689, the claim was drawn to "The method of treating a malignant condition selected from the group consisting of leukemias, sarcomas, adenocarcinomas, lymphosarcomas, melanomas, myelomas, and ascitic tumors" using a small genus of compounds. The Court decided that human testing "limited to one compound and two types of cancer" was not "commensurate with the broad scope of utility asserted and claimed".
In Ex parte Jovanovics, 211 USPQ 907 the claims were drawn to "the treatment of certain specified cancers in humans" by the use of a genus of exactly two compounds, the N-formyl or N-desmethyl derivative of leurosine. Applicants submitted "affidavits, publications and data" for one of the compounds, and a dependent claim drawn to the use of that species was allowed. For the other, no data was presented, applicants said only that the other derivative would be expected to be less effective; claims to the genus were refused.
In Ex parte Busse, et al., 1 USPQ2d 1908, claims were drawn to "A therapeutic method for reducing metastasis and neoplastic growth in a mammal" using a single species. The decision notes that such utility "is no longer considered to be "incredible", but that "the utility in question is sufficiently unusual to justify the examiner's requirement for substantiating evidence. Note also that there is also a dependent claim 5 which specified "wherein metastasis and neoplastic growth is adenocarcinoma, squamous cell carcinoma, melanoma, cell small lung or glioma." The decision notes that "even within the specific group recited in claim 5 some of the individual terms used actually encompass a relatively broad class of specific types of cancer, which specific types are known to respond quite differently to various modes of therapy."
In Ex parte Stevens, 16 USPQ2d 1379 a claim to "A method for therapeutic or prophylactic treatment of cancer in mammalian hosts" was refused because there was "no actual evidence of the effectiveness of the claimed composition and process in achieving that utility."
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required: (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. Some experimentation is not fatal; the issue is whether the amount of experimentation is "undue"; see In re Vaeck, 20 USPQ2d 1438, 1444.
The analysis is as follows:
1) Breadth of claims.
"Cancer" is not a single disease, or cluster of closely related disorders. There are hundreds of cancers, which have in common only some loss of controlled cell growth. Cancers are highly heterogeneous at both the molecular and clinical level, something seen especially in, for example, the cancers of the breast, brain and salivary glands. They can occur in pretty much every part of the body. To be able to simply stop cancer cells generally from being able to proliferate. Many of these approaches --- and there have been others as well --- have produced anti-cancer drugs. However, despite high hopes for success, and a plausible theory why these should work for cancers generally, none of these approaches have ever produced a drug which come remotely near such a goal.
Specifically, the prior art knows that there never has been a compound capable of treating cancers generally. "The cancer therapy art remains highly unpredictable, and no example exists for efficacy of a single product against tumors generally." (<http://www.uspto.gov/web/offices/pac/dapp/1pecba.htm#7> ENABLEMENT DECISION TREE, Example F, situation 1). A similar statement appears at In re Application of Hozumi et al., 226 USPQ 353: "In spite of the vast expenditure of human and capital resources in recent years, no one drug has been found which is effective in treating all types of cancer. Cancer is not a simple disease, nor is it even a single disease, but a complex of a multitude of different entities, each behaving in a different way". There are compounds that treat a modest range of cancers, but no one has ever been able to figure out how to get a compound to be effective against cancer generally, or even a majority of cancers.
The attempts to find compounds to treat the various cancers arguably constitute the single most massive enterprise in all of pharmacology. This has not resulted in finding any treatment for tumors generally. Indeed, the existence of such a "silver bullet" is contrary to our present understanding in oncology. This is because it is now understood that there is no "master switch" for cancers generally; cancers arise from a bewildering variety of differing mechanisms. Even the most broadly effective antitumor agents are only effective against a small fraction of the vast number of different cancers known. This is true in part because cancers arise from a wide variety of sources, primarily a wide variety of failures of the body's cell growth regulatory mechanisms, but also such external factors such as viruses (an estimated at least 20% are of viral origin e.g. Human papillomavirus, EBV, Hepatitis B and C, HHV-8, HTLV-1 and other retroviruses, and quite possibly Merkel cell polyomavirus, and there is some evidence that CMV is a causative agent in glioblastoma), exposure to chemicals such as tobacco tars, excess alcohol consumption (which causes hepatic cirrhosis, an important cause of HCC), ionizing radiation, and unknown environment factors.
Accordingly, there is substantive "reason for one skilled in the art to question the objective truth of the statement of utility or its scope" (In re Langer, 183 USPQ 288, 297), specifically, the scope of covering cancer generally.
Similarly, In re Novak, 134 USPQ 335, 337-338, says "unless one with ordinary skill in the art would accept those allegations as obviously valid and correct, it is proper for the examiner to ask for evidence which substantiates them." There is no such evidence in this case. Likewise, In re Cortright, 49 USPQ2d 1464, states: "Moreover, we have not been shown that one of ordinary skill would necessarily conclude from the information expressly disclosed by the written description that the active ingredient" does what the specification surmises that it does. That is exactly the case here. Moreover, even if applicants' assertion that cancer in general could be treated with these compounds were plausible --- which it is not ---, that "plausible" would not suffice, as was stated in Rasmusson v. SmithKline Beecham Corp., 75 USPQ2d 1297, 1301: "If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to "inventions" consisting of little more than respectable guesses as to the likelihood of their success."
Different types of cancers affect different organs and have different methods of growth and harm to the body, and different vulnerabilities. The skill thus depends on the particular cancer involved. There are some cancers where the chemotherapy skill level is high and there are multiple successful chemotherapeutic treatments. The mechanism in these situations, however, is not necessarily the same as is alleged for these compounds.
One skilled in the art knows that chemotherapy of brain tumors is especially difficult. This is because 1) the blood-brain barrier, which is often intact in parts or all of a brain tumor, will block out many drugs, as it is the purpose of the blood-brain barrier to protect the brain from alien chemicals, and 2) CNS tumors are characterized by marked heterogeneity, which greatly decreases vulnerability to chemotherapy. As a result, many categories of CNS tumors simply have no chemotherapy available. These include, generally, hemangioblastomas, meningiomas, craniopharyngiomas, acoustic neuromas, pituitary adenomas, optic nerve gliomas, glomus jugulare tumors and chordomas, to name just some. With regard to gliomas, GBM is considered untreatable; no effective agents have emerged for the treatment of GBM, despite 20 years of enrolling patients in clinical trials. It is radiation and surgery which are used for low grade gliomas (e.g. pilocytic astrocytoma and diffuse astrocytomas), as no drug has been found effective. There is no drug treatment established as effective for optic nerve gliomas or gangliogliomas. Indeed, very few gliomas of any type are treated with pharmaceuticals; it is one of the categories of cancer that is the least responsive to drugs.
Lymphomas of the stomach are not commonly treated with anti-cancer agents per se, but instead, surgery or radiation and antibiotic therapy (e.g. amoxicillin, metronidazole, bismuth, and omeprazole) are the primary treatments.
Neuroendocrine tumors of the cervix generally do not respond to chemotherapy.
A number of sarcomas, including alveolar soft part sarcoma (ASPS), retroperitoneal sarcoma, most liposarcomas, and the assorted chondrosarcomas, are generally considered not to respond to chemotherapy; no chemotherapeutic agent has been established as effective.
It is important to note that tumors can need to be treated quite differently even though they are tumors of the same organ. For example, the drugs used most often to treat Wilms tumor, the most common malignant tumor of the kidneys in children, are actinomycin D and vincristine. Such drugs are never used with clear cell renal carcinoma, which is treated, although without much success, with immunotherapy using the cytokines interleukin-2 and interferon-alpha. However, such immunotherapy has never been established as effective in non-clear cell RCC forms such as papillary renal cell carcinoma. Despite strenuous efforts over a period of decades, no chemotherapeutic agent has ever been found effective against this cancer. Cancers of the stomach can be lymphomas, GISTs, carcinoid tumors, carcinomas, or soft tissue sarcomas, and for a single agent to be effective against all or even most of these categories would be contrary to what is known in oncology.
The scope of treating inflammation generally is extraordinarily broad. Inflammation is a process which can take place in virtually any part of the body. There is a vast range of forms that it can take, causes for the problem, and biochemical pathways that mediate the inflammatory reaction. It is one of the most pervasive of all body processes. Inflammation is a very general term which encompasses a huge variety of specific processes.
2) The nature of the invention and predictability in the art.
With specific reference to cancer, Ex parte Kranz, 19 USPQ2d 1216, 1219 notes the "general unpredictability of the field [of] …anti-cancer treatment." In re Application of Hozumi et al., 226 USPQ 353 notes the "fact that the art of cancer chemotherapy is highly unpredictable". More generally, the invention is directed toward medicine and is therefore physiological in nature. It is well established that "the scope of enablement varies inversely with the degree of unpredictability of the factors involved," and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
3) State of the Prior Art.
The claimed compounds Compounds 1, 2, 3, 3a, 3b, 4, 4a, 4b, 5, 6, 6a, 6b, and 7 in combination with other therapeutic agents. So far as the examiner is aware these compounds and combinations have not been successfully used as broad range anticancer agents involving inhibition of SOS1.
4) Working Examples. Applicants have provided no working examples which are successfully used as broad range anticancer agents. Applicants have, however, demonstrated the cytotoxicity of the claimed SOS1 inhibitors in combination with AMG510, afatinib, LY3214996, BVD-523, encorafenib, Compound 24 of WO2019116302, LXH254, TNO155, MRTX849, BYL-719, GSK3368715, nintedanib, abemaciclib, MRTX1133, and Gemcitabine in pancreatic cancer cells and xenograft models. See Figs. 1-41 and specification p. 184-188.
5) Skill of those in the art.
Many, many mechanisms have been proposed over the decades as methods of treating the assorted cancers generally. Cytotoxic agents could be applied directly to the tumor cells, directly killing them. Immunotherapy involves stimulating the patient’s immune system to attack cancer cells generally, either by immunization of the patient, in which case the patient’s own immune system is trained to recognize tumor cells as targets, or by the administration of therapeutic antibodies as drugs, so the patient’s immune system is recruited to destroy tumor cells by the therapeutic antibodies. Another approach would be to increase the amount or activity of the body’s tumor suppressor genes, e.g. p53, PTEN, APC and CD95, which can for example activate DNA repair proteins, suppress the Akt/PKB signaling pathway, or initiate apoptosis of cancer cells. The angiogenesis inhibitor strategy was based on cutting off the blood supply that growing tumors need by shutting off the growth of new blood vessels by, for example, suppressing proliferation of endothelial cells or inducing apoptosis of endothelial cells. There is also the cancer stem cell paradigm, which hypothesizes that cancer could be treated generally, either by targeting the cancer stem cells themselves, or by targeting the epithelial-to-mesenchymal transition which supposedly generates the cancer stem cells. Yet another approach is to inhibit one or more of the assorted HSP90 proteins, which will supposedly disrupt the proper folding of signaling proteins that all cancers rely on. Inhibiting telomerase was said to be able to be able to simply stop cancer cells generally from being able to proliferate. Many of these approaches --- and there have been others as well --- have produced anti-cancer drugs. However, despite high hopes for success, and a plausible theory why these should work for cancers generally, none of these approaches have ever produced a drug which come remotely near such a goal.
Accordingly, there is substantive “reason for one skilled in the art to question the objective truth of the statement of utility or its scope” (In re Langer, 183 USPQ 288, 297), specifically, the scope of covering cancer generally. Moreover, even if applicants’ assertion that cancer in general could be treated with these compounds were plausible --- which it is not ---, that “plausible” would not suffice, as was stated in Rasmusson v. SmithKline Beecham Corp., 75 USPQ2d 1297, 1301: “If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to “inventions” consisting of little more than respectable guesses as to the likelihood of their success.”
6) Scope of the claims. The scope of the claims involves the combination of species of SOS1 inhibitors with one or more agents selected from an EGFR inhibitor, KRAS inhibitor, ERK1/2 inhibitor, RAF inhibitor, PRMT5 inhibitor, pan-RAF inhibitor, SHP2 inhibitor, AKT inhibitor, PI3K inhibitor, Type I PRMT inhibitor, FGFR inhibitor, CDK4/6 inhibitor, c-Met inhibitor, PD1/PD-L1 inhibitor, CTLA-4 inhibitor, and Chemotherapeutic agent, and their use as potential treatment of cancers involving inhibition of SOS1. Thus, the scope of the claims is very broad.
7) The quantity of experimentation needed. Given the fact that, historically, the development of new cancer drugs has been difficult and time consuming, and especially in view of factors 1 and 4 and 6, the quantity of experimentation needed is expected to be great.
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).” That conclusion is clearly justified here.
Claims 42, 44, and 49-55 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 Sotorasib (AMG510), MRTX849, JDQ443, LY-3537982, JNJ-74699157, JAB-21822, GDC-6036, D-1553, YL-15293, BI-1823911, BEBT-607, MRTX1133, BI-2852, LY3214996, BVD-523, Afatinib, Encorafenib, Compound 24 of WO 2019116302, LXH254, TNO155, BYL-719, GSK3368715, Nintedanib, Abemaciclib, and Gemcitabine, does not reasonably provide enablement for . 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 or use the invention commensurate in scope with these claims.
The instant invention is directed toward a combination of an SOS1 inhibitor with at least one agent selected from an EGFR inhibitor, KRAS inhibitor, ERK1/2 inhibitor, RAF inhibitor, PRMT5 inhibitor, pan-RAF inhibitor, SHP2 inhibitor, AKT inhibitor, PI3K inhibitor, Type I PRMT inhibitor, FGFR inhibitor, CDK4/6 inhibitor, c-Met inhibitor, PD1/PD-L1 inhibitor, CTLA-4 inhibitor, or Chemotherapeutic agent, and their use in treating or preventing cancer. The specification provides particular species of the above inhibitors but does not define that which is intended in the use of each genus generally. While there are hundreds of anti-cancer agents known in the art, there is no evidence that each and every EGFR inhibitor, KRAS inhibitor, etc. could be combined with the claimed SOS1 inhibitors to treat cancer. Combination treatments and the treatment of cancer generally are considered unpredictable in the art (see previous rejection). Combinations of agents can be antagonistic, additive, synergistic, or have no change in effect. This cannot be determined without testing each and every agent at numerous possible doses and/or concentrations. The working examples only test the agents for which Applicant is enabled.
The applicants may only claim whatever he or she regards as his or her invention, i.e., the applicant may not claim subject matter that he or she does not regard as his or her invention. The applicants are not entitled to preempt the efforts of others in future discoveries, wherein the claims are directed toward agents that have yet to be discovered. The applicants are only entitled to those additional active ingredients, i.e., anti- cancer agents, contemplated at the time of filing. Where the utility is unusual or difficult to treat or speculative, such as in the case of treating cancer, the examiner has authority to require evidence that tests relied upon are reasonably predictive of in vivo efficacy by those skilled in the art. See In re Ruskin, 148 USPQ 221; Ex parte Jovanovics, 211 USPQ 907; MPEP 2164.05(a). 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. In re Wright, 999 F.2d 1557, 1561 27 USPQ2d 1510, 1513 (Fed. Cir. 1993). That conclusion is justified here.
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.
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.
Claim(s) 42-45 and 49-55 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kurhade et al. (WO 2021/130731 A1; IDS) in view of Hong et al. (The New England Journal of Medicine; 2020; IDS) and Hofmann et al. (WO 2021/259972 A1; IDS).
Kurhade et al. discloses each of compounds 1, 2, 3, 3a, 3b, 4, 4a, 4b, 6, 6a, 6b, and 7 (p. 235, 242, 244, 246, 281-282, 297-298, 369). Kurhade et al. discloses that the compounds are SOS1 inhibitors that inhibit KRAS-SOS1 interaction in mutant KRAS G12C (p. 3, 380-382). Kurhade et al. discloses that the compounds inhibit ERK phosphorylation in colorectal cancer cells (p. 382-383) and inhibit the growth of tumors in pancreatic cancer xenografts (p. 384). Kurhade et al. discloses that the compounds can be combined with other agents including KRAS inhibitors (p. 5, line 25). Cancers contemplated by Kurhade et al. to be treated with the compounds include pancreatic cancer, colorectal cancer, and lung cancer (p. 17, lines 7-8).
Kurhade et al. does not teach a combination of the disclosed compounds with sotorasib (AMG510) or a method of treating cancer comprising administering a composition comprising a SOS1 inhibitor selected from one of compounds 1, 2, 3, 3a, 3b, 4, 4a, 4b, 6, 6a, 6b, and 7 and sotorasib (AMG510). Kurhade et al. does not teach administering the SOS1 inhibitor simultaneously, concurrently, sequentially, successively, alternately, or separately with the additional therapeutic agent. These limitations are obvious over Hong et al. and Hofmann et al.
Hong et al. discloses a method of treating non-small cell lung cancer (NSCLC) and colorectal cancer in patients with the KRAS G12C mutation comprising administering an escalating dose of sotorasib, a KRAS G12C inhibitor (Abstract; p. 1208). Hong et al. additionally discloses that one patient had pancreatic cancer and partially responded to treatment (p. 1215 col. 1). Hong et al. additionally suggests evaluating sotorasib in combination with other agents (p. 1216 col. 2).
Hofmann et al. discloses a combination of a SOS1 inhibitor and a KRAS G12C inhibitor for treatment of cancer, and a method of treating cancer comprising administering the combination (p. 6, lines 10-14). Hofmann et al. discloses sotorasib (AMG510) as a preferred KRAS G12C inhibitor (p. 12-13). Hofmann et al. discloses that administration of the SOS1 inhibitor and KRAS G12C inhibitor can be simultaneous, concurrent, sequential, successive, alternate, or separate (p. 19, lines 17-24). Hofmann et al. particularly points to cancers such as pancreatic cancer, lung cancer (non-small cell lung cancer), and colorectal cancer as cancers in need of treatment options and to be treated with the disclosed combination (p. 4, lines 26-28; p. 23, lines 18-22).
It would be prima facie obvious for one of ordinary skill in the art to combine a SOS1 inhibitor as in Kurhade et al. with sotorasib (AMG510) for the treatment of cancer or in a method of treating cancer, particularly wherein the cancer is NSCLC, colorectal cancer, or pancreatic cancer. One would have been motivated to do so, with reasonable expectation of success, because both agents demonstrate efficacy against these overlapping cancers individually and Hofmann et al. particularly teaches that SOS1 inhibitors and KRAS G12C inhibitors can be combined for the treatment of NSCLC, colorectal cancer, and pancreatic cancer.
Moreover, it would be prima facie obvious for one of ordinary skill in the art to administer the SOS1 inhibitor of Kurhade et al. with sotorasib simultaneously, concurrently, sequentially, successively, alternately, or separately. One would have been motivated to try, given a list of predictable solutions, in order to ascertain the optimal order of administration for treatment of cancer.
Claim(s) 42-43, 49-51, and 55 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sethi et al. (WO 2021/105960 A1) in view of Hong et al. (The New England Journal of Medicine; 2020; IDS) and Hofmann et al. (WO 2021/259972 A1; IDS).
Sethi et al. teaches compound 5 (p. 170, compound 87). Sethi et al. teaches that the disclosed compounds are SOS1 inhibitors that inhibit KRAS-SOS1 interaction in mutant KRAS G12C (p. 1; p. 229-232). Sethi et al. discloses that the compounds inhibit ERK phosphorylation in colorectal cancer cells (p. 232-233), inhibit colony formation in colorectal and pancreatic cancer cells (p. 233, particularly compound 87), and inhibit the growth of tumors in pancreatic cancer xenografts (p. 235). Sethi et al. discloses that the compounds can be combined with other agents including KRAS G12C inhibitors (p. 6, line 26; p. 233). Cancers contemplated by Sethi et al. to be treated with the compounds include pancreatic cancer, colorectal cancer, and lung cancer (p. 5).
Sethi et al. does not teach a combination of the disclosed compounds with sotorasib (AMG510) or a method of treating cancer comprising administering a composition comprising a SOS1 inhibitor selected from one of compounds 1, 2, 3, 3a, 3b, 4, 4a, 4b, 6, 6a, 6b, and 7 and sotorasib (AMG510). Sethi et al. does not teach administering the SOS1 inhibitor simultaneously, concurrently, sequentially, successively, alternately, or separately with the additional therapeutic agent. These limitations are obvious over Hong et al. and Hofmann et al.
Hong et al. discloses a method of treating non-small cell lung cancer (NSCLC) and colorectal cancer in patients with the KRAS G12C mutation comprising administering an escalating dose of sotorasib, a KRAS G12C inhibitor (Abstract; p. 1208). Hong et al. additionally discloses that one patient had pancreatic cancer and partially responded to treatment (p. 1215 col. 1). Hong et al. additionally suggests evaluating sotorasib in combination with other agents (p. 1216 col. 2).
Hofmann et al. discloses a combination of a SOS1 inhibitor and a KRAS G12C inhibitor for treatment of cancer, and a method of treating cancer comprising administering the combination (p. 6, lines 10-14). Hofmann et al. discloses sotorasib (AMG510) as a preferred KRAS G12C inhibitor (p. 12-13). Hofmann et al. discloses that administration of the SOS1 inhibitor and KRAS G12C inhibitor can be simultaneous, concurrent, sequential, successive, alternate, or separate (p. 19, lines 17-24). Hofmann et al. particularly points to cancers such as pancreatic cancer, lung cancer (non-small cell lung cancer), and colorectal cancer as cancers in need of treatment options and to be treated with the disclosed combination (p. 4, lines 26-28; p. 23, lines 18-22).
It would be prima facie obvious for one of ordinary skill in the art to combine the SOS1 inhibitor as in Sethi et al. with sotorasib (AMG510) for the treatment of cancer or in a method of treating cancer, particularly wherein the cancer is NSCLC, colorectal cancer, or pancreatic cancer. One would have been motivated to do so, with reasonable expectation of success, because both agents demonstrate efficacy against these overlapping cancers individually and Hofmann et al. particularly teaches that SOS1 inhibitors and KRAS G12C inhibitors can be combined for the treatment of NSCLC, colorectal cancer, and pancreatic cancer.
Moreover, it would be prima facie obvious for one of ordinary skill in the art to administer the SOS1 inhibitor of Sethi et al. with sotorasib simultaneously, concurrently, sequentially, successively, alternately, or separately. One would have been motivated to try, given a list of predictable solutions, in order to ascertain the optimal order of administration for treatment of cancer.
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€ 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€ 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.
Claims 42-43, 49-51, and 55 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 17, 19-20, and 24-27 of U.S. Patent No. 12435066 B2 in view of Hong et al. (The New England Journal of Medicine; 2020; IDS) and Hofmann et al. (WO 2021/259972 A1; IDS).
The claims of the ‘066 patent are directed toward compounds including instantly claimed compound 5 (see claim 17). The claims further recite methods of treating cancers, including pancreatic cancer, colorectal cancer, and lung cancer, comprising administering the claimed compounds or a combination of a claimed compound and a pharmaceutically active agent.
Hong et al. and Hofmann et al. teach as above.
For the same reasons as in the above 103 rejections, it would have been prima facie obvious for one of ordinary skill in the art to arrive at the instant invention in view of Hong et al. and Hofmann et al.
Response to Arguments
Applicant’s arguments in the Remarks filed 06/26/2026 have been considered by Examiner, but they are not persuasive.
35 U.S.C. 112(b)
On page 10 of the remarks, Applicant states “Claims 50 and 53 are amended to address antecedent basis issues”. However, the amendments are not sufficient to overcome the rejection of claims 50 and 53 for lack of antecedent basis of “the subject in need”. Claims 50 and 53 have been amended to recite “the subject in need thereof”. This limitation still lacks antecedent basis as the claims contain no earlier recitation or limitation of “a subject in need thereof”, thus it is unclear what “the subject in need thereof” refers to. Examiner has suggested a correction to the claims in the above rejection.
35 U.S.C. 112(a)
On pages 11-14 of the remarks, Applicant argues that the invention is enabled for treatment of specific cancers, wherein the claims at issue have been limited to treatment of specific cancers (p. 11-13). This is not persuasive. First, while claims 42-45 and 49-56 were previously rejected, only claims 50 and 53 have been amended, while claim 42 is still generally directed toward a combination “for treating cancer”. Additionally, claims 50 and 53 have been amended to recite “A method of treating cancer involving inhibition of SOS1”. While Applicant argues that the claims have been limited to treatment of specific cancers, the claims as they are amended can be interpreted far more generously, wherein “involving inhibition of SOS1” broadly reads on treating cancers by inhibiting SOS1, which favors limiting the mechanism of treatment rather than the condition to be treated.
As in the above rejection, the treatment of cancers is unpredictable. Absent substantial evidence, one cannot purport that a compound or combination of compounds would be capable of treating cancer generally via pathways “involving inhibition of SOS1”. The majority of cancers would not be expected to respond by inhibiting SOS1 by mere plausibility. For example, there is no evidence that the claimed combinations are capable of crossing the blood-brain barrier. Moreover, there are numerous variables and mechanisms by which cancer may develop resistance to treatment.
Applicant additionally argues that the specification provides extensive data demonstrating efficacy of SOS1 inhibitors in combination with multiple representative agents, and that experimentation required would be considered routine and not undue (p. 14 of remarks). Looking to the specification, Example 8 sets forth in vitro experiments wherein the claimed SOS1 compounds are combined with one or more agents in pancreatic cancer cells. These agents are limited to at most two species of each of an EGFR inhibitor, KRAS-G12C inhibitor, KRAS-G12D inhibitor, ERK1/2 inhibitor, BRAF inhibitor, pan-RAF inhibitor, PRMT5 inhibitor, type I PRMT inhibitor, PI3K inhibitor, FGFR inhibitor, CDK4/6 inhibitor, and Gemcitabine. Testing a supposedly representative species of each inhibitor fails to account for the different mechanisms by which species may inhibit their respective pathways. For example, can one predict that an indirect inhibitor would yield the same results as a direct inhibitor? Would an agent with no demonstrated efficacy against the KRAS-SOS1 pathway in mutant KRAS G12C cancers be routinely combinable with the claimed SOS1 inhibitors?
Notably, no examples of a c-MET inhibitor, a PD1/PD-L1 inhibitor, or a CTLA-4 inhibitor are disclosed, yet Applicant argues that the “predictable nature of pathway-based combination therapies” would enable one of ordinary skill to practice the claimed invention by routine experimentation. However, later in Applicant’s arguments (p. 16, regarding the rejection under 35 U.S.C. 103), Applicant states “Oncology combination therapies are well recognized as unpredictable, and a general overlap in biological pathways does not render specific combinations obvious”. Applicant’s arguments are evidently contradictory and fail to support the allegation that combining such a broad genus of agents with the claimed SOS1 inhibitors would be routine practice. The rejections are maintained.
35 U.S.C. 103 and Double Patenting
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
Per MPEP 2143.01, “A ‘motivation to combine may be found explicitly or implicitly in market forces; design incentives; the ‘interrelated teachings of multiple patents’; ‘any need or problem known in the field of endeavor at the time of invention and addressed by the patent’; and the background knowledge, creativity, and common sense of the person of ordinary skill.’ Zup v. Nash Mfg., 896 F.3d 1365, 1371, 127 USPQ2d 1423, 1427 (Fed. Cir. 2018) (quoting Plantronics, Inc. v. Aliph, Inc., 724 F.3d 1343, 1354 [107 USPQ2d 1706] (Fed. Cir. 2013) (citing Perfect Web Techs., Inc. v. InfoUSA, Inc., 587 F.3d 1324, 1328 [92 USPQ2d 1849] (Fed. Cir. 2009) (quoting KSR, 550 U.S. at 418-21).” In the instant case, one would have been apprised as to the need for additional cancer treatments, wherein the cited prior art documents either explicitly or implicitly suggest the benefit of combining SOS1 inhibitors with KRAS G12C inhibitors such as sotorasib for the treatment of cancers.
Applicant additionally argues that no reasonable expectation of success is established, stating “Oncology combination therapies are well recognized as unpredictable, and a general overlap in biological pathways does not render specific combinations obvious” (p. 16 of remarks). As noted previously, this statement is directly contradicted by Applicant earlier in their arguments. Moreover, the combination of references does more than establish a “general overlap” in biological pathways to suggest the combination of the claimed SOS1 inhibitors with sorafenib. Kurhade et al., for example, discloses that the SOS1 inhibitors inhibit the interaction of KRAS and SOS1, indicating that KRAS and SOS1 share a pathway rather than merely overlap.
Moreover, while Applicant argues that the working examples provide evidence of unexpected results, the scope of the instant claims is substantially broader than those of the working examples. Per MPEP 716.02(d), “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the ‘objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.’ In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980).” While the instant claims are drawn to generic groups of inhibitors and cancer generally, the working examples are limited to demonstrating enhanced effects in pancreatic cancer by combining the claimed SOS1 inhibitors with afatinib, AMG 510, MRTX849, MRTX1133, LY3214996, BVD-523, encorafenib, LXH254, compound 24 of WO 2019116302, GSK3368715, BYL719, nintedanib, abemaciclib, or gemcitabine. The evidence based on these results, which extend to only one or two species within each genus of additional therapeutic agent, would not allow one of ordinary skill in the art to extend the probative value of the results across the full scope of the claimed invention. The rejection is maintained.
For the same reasons, the nonstatutory double patenting rejection above is also maintained.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MADELINE E BRAUN whose telephone number is (703)756-4533. The examiner can normally be reached M-F 8:30am-5:00pm ET.
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/M.E.B./Examiner, Art Unit 1624 07/16/2026
/BRENDA L COLEMAN/Primary Examiner, Art Unit 1624
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