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 .
Election/Restrictions
Applicant's election with traverse of a species of SOS1 inhibitor that is Compound 7 and a species of additional active ingredient that is AMG510 in the reply filed on 12/01/2025 is acknowledged. The traversal is on the ground(s) that claims 1-41 have been cancelled and newly added claims 42-56 do not require an SOS1 inhibitor of Formula (I) or (II) and instead provides a list of species of SOS1 inhibitors, wherein the SOS1 inhibitor compounds are combined with an additional therapeutic agent. This is persuasive with regards to the election of species requirement of a species of SOS1 inhibitor, as the art cited in the Office Action mailed 10/01/2025 does not teach the newly claimed species of SOS1 inhibitors. The requirement for election of a species of SOS1 inhibitor is withdrawn. However, Applicant’s arguments are not found persuasive with regards to the additional therapeutic agent because the genus of additional therapeutic agents do not make a contribution over the prior art. This much is admitted by Applicant in the Remarks filed 12/01/2025 on page 8.
The requirement to elect a species of additional therapeutic agent is still deemed proper and is therefore made FINAL.
Claims 46-48 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species of additional therapeutic agent, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 12/01/2025.
Priority
Examiner acknowledges that, according to the Filing receipt received 06/04/2024, that the instant application 18/262,155 filed 07/19/2023 is a 371 of PCT/IB2022/050415 filed 01/19/2022, which claims foreign priority of application IN202121002487 filed 01/19/2021.
However, the limitations of the instant claims are not adequately supported or enabled in the manner provided by 35 U.S.C. 112(a) or pre-AIA U.S.C. 112, first paragraph by IN202121002487. More specifically, the limitations of Compound 7 are not taught or suggested. As such, all the instant claims have been awarded the effective filing date of PCT/IB2022/050415 filed 01/19/2022.
Information Disclosure Statement
The Information Disclosure Statements filed on 01/05/2024 are in compliance with the provisions of 37 CFR 1.97 and have been considered in full. A signed copy of list of references cited from the IDS is included with this Office Action.
Specification
The disclosure is objected to because of the following informalities:
Page 49, line 4: “WO200879759.Compound” should read “WO200879759. Compound”;
Page 53: line 2 does not end in a period;
Page 167, line 16: close parenthesis “)” is missing;
Appropriate correction is required.
The 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.
The incorporation of essential material in the specification by reference to an unpublished U.S. application, foreign application or patent, or to a publication is improper. Applicant is required to amend the disclosure to include the material incorporated by reference, if the material is relied upon to overcome any objection, rejection, or other requirement imposed by the Office. The amendment must be accompanied by a statement executed by the applicant, or a practitioner representing the applicant, stating that the material being inserted is the material previously incorporated by reference and that the amendment contains no new matter. 37 CFR 1.57(g).
Claim Objections
Claims 42, 50, and 53 are objected to because of the following informalities:
Claim 42: “R/S)” should read “(R/S)”;
Claim 42: "one or more additional therapeutic agent" should read "one or more additional therapeutic agents";
Claims 50 and 53: “comprising” should read “comprises”.
Appropriate correction is required.
Applicant is advised that should claim 55 be found allowable, claim 56 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. Claims 55 and 56 both depend on claim 51 and recite the same limitations. Should claim 56 depend on claim 54? When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
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 43-45, 50-51, and 53-56 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.
Claim 43 depends on claim 41, however, claim 41 has been cancelled. Claim 43 therefore lacks antecedent basis. For purposes of examination, Examiner has interpreted claim 43 as if it depends on claim 42.
Claims 43 and 44 recite “Compound 24 of WO 2019116302”. The claims should be complete in and of themselves. MPEP 2173.05(s). Moreover, essential material cannot be incorporated by reference from a foreign application. 37 CFR 1.57(g). The scope of Compound 24 is therefore unclear. Examiner suggests that Applicant replace “Compound 24 of WO 2019116302” with the name or structure of said compound. Claim 45 is similarly rejected for requiring the limitation at issue.
Claims 50 and 53 recite “the subject in need”. This limitation lacks antecedent basis. Claims 51 and 54-56 are rejected for requiring the limitation at issue.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 49 and 52 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 49 depends on claim 42. Claim 52 depends on claim 44. Both claims 49 and 52 recite an intended use of the claimed pharmaceutical combinations. Since intended use is given minimal patentable weight, claims 49 and 52 fail to further limit the claims from which they depend. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 49-56 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 preventing any cancer or treating cancers generally. 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.
It is presumed “prevention” of the claimed disease would require a method of identifying those individuals who will develop the claimed diseases before they exhibit symptoms. There is no evidence of record that would guide the skilled clinician to identify those who have the potential of becoming afflicted.
"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 state of the art is that no general procedure is art-recognized for determining which patients generally will suffer from cancer before the fact.
The claimed compounds are of Formula (A). So far as the examiner is aware these compounds have not been successfully used as broad range anticancer agents.
4) Working Examples. Applicants have provided no working examples which are successfully used as broad range anticancer agents or agents for preventing cancer. 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. The artisan using Applicants invention would be a Board-Certified physician in oncological diseases with an MD degree. Despite intensive efforts, pharmaceutical science has been unable to find a way of getting a compound to be effective for the prevention of SSADHD. Under such circumstances, it is proper for the PTO to require evidence that such an unprecedented feat has actually been accomplished, In re Ferens, 163 USPQ 609. No such evidence has been presented in this case. The failure of skilled scientists to achieve a goal is substantial evidence that achieving such a goal is beyond the skill of practitioners in that art, Genentech vs. Novo Nordisk, 42 USPQ2nd 1001, 1006. This establishes that it is not reasonable for any agent or combination of agents to be able to prevent cancer.
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 or prevention of cancers. 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 49-56 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 49-56 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 55-56 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(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.
Claims 42-43, 49-51, and 55-56 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.
Claims 42-45 and 49-56 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 14-15 of copending Application No. 17/789,293 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 ‘293 application are directed toward compounds including instantly claimed compounds 1, 2, 3, 3a, 3b, 4, 4a, 4b, 6, 6a, 6b, and 7 (see claim 14) and compositions thereof.
When making obviousness-type double patenting decisions, the Federal Circuit has stated, “[O]bviousness-type double patenting encompasses any use for a compound that is disclosed in the specification of an earlier patent claiming the compound and is later claimed as a method of using that compound”. Sun Pharm. Indus., Ltd. v. Eli Lilly & Co., 611 F.3d 1381 (Fed. Cir. 2010).
The specification of the ‘293 application discloses that the compounds can be combined with other agents including KRAS inhibitors (p. 5, line 25) and can be used to treat cancers including pancreatic cancer, colorectal cancer, and lung cancer (p. 17, lines 7-8).
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.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/M.E.B./Examiner, Art Unit 1624 12/18/2025
/BRENDA L COLEMAN/Primary Examiner, Art Unit 1624