Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
This office action is response to communication filed on 08/14/2025.
Election/Restriction
In the reply filed on 08/14/2025, Applicant elected without traverse Group II, claims 57-64, drawn to methods of treatment; and species :
1) compound of formula (I): 2- ((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptan-7-yl)-5-(3,4-dichloro-2- methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4- one (claim 51);
2) additional antitumor agent: cetuximab.
3) species of tumor: epithelial cancer.
Claims 57- 64 read on the elected invention and species.
Group I, claims 49-56 and 65 are withdrawn from further consideration as being directed to non-elected inventions.
The elected compound species, 2- ((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptan-7-yl)-5-(3,4-dichloro-2- methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4- one (claim 60), having following structure,
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, is disclosed as Compound 1 in instant speciation (See [0148] of WO2121149817). The elected compound species is compound of Formula I recited in claim 57 ,
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wherein Ring A is
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, a is 0, X is CH, Q is C, R1 is CH3, R2 and R3 forming a C3 alkylene bridge group, R4 is amino, R5, R6 and R7 is H.
The elected species, Compound 1, 2- ((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptan-7-yl)-5-(3,4-dichloro-2- methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4- one ( CAS# 2409578-43-2, entered STN database on February 14, 2020), is rejected under 102 and 103 rejection in this office action. Other non-elected species are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected species. It should be noted that prior art search will not be extended unnecessarily to cover all non-elected species. Should Applicant overcome the rejection by amending the claim, the amended claim will be reconsidered. The prior art search will be extended to the extent necessary to determine patentability of the Markush-type claim. In the event prior art is found during reconsideration that renders obvious or anticipates the amended Markush-type claim, the claim will be rejected and the action made final.
Status of Claims
Claims 49-65 are pending in the instant application.
Claims 49-56 and 65 are withdrawn, being drawn to nonelected inventions/species.
Claims 57- 64 are currently under examination.
Priority
This instant application 17/759,335 filed on 07/22/2022 is a national stage of International Application No. PCT/JP2021/002318, filed on January 22, 2021, which claims priority to Japanese Application No. 2020-010300, filed on January 24, 2020, and Japanese Application No. 2020-168593, filed on October 5, 2020. The certified copy of Japanese Application No. 2020-010300 and 2020-168593 are filed on 07/22/2022.
Information Disclosure Statement
The information disclosure statements filed on 01/03/2023, 01/06/2023, 03/24/2023, 04/19/2023, 06/22/2023, 09/19/2023, 01/13/2024, 02/09/2024, 03/04/2024, 08/15/2024, 08/30/2024, 09/12/2024, 10/17/2024, 01/10/2025, 02/13/2025 and 08/05/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the relevant reference listed in IDS are being considered by the examiner. Reference written in foreign language are considered to the degree of English abstract or patent family of foreign patent.
Claim Objections
Instant claims 57, 58 and 61 recite limitation at least one additional compound having an antitumor effect, at least one tautomer thereof, at least one solvate thereof, or at least one pharmaceutically acceptable salt thereof…. The recitation of “at least one tautomer thereof, at least one solvate thereof, or at least one pharmaceutically acceptable salt thereof” is repetitive and confusing. Please note not all compound having antitumor effect would have tautomer or solvate or salt thereof.
Specification
Instant specification disclosed vast variety of chemical compounds with complex structures and lengthy names. 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.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 57-64 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 a method for treating certain tumor/cancer (e.g. colorectal cancer) associated with SHP2 (Src homology-2 domain-containing protein
tyrosine phosphatase-2) with the elected compound 1, 2- ((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptan-7-yl)-5-(3,4-dichloro-2- methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4- one, in combination with certain antitumor compound /molecular targeted drug/kinase inhibitor (e.g. cetuximab) at specific dose/concentration, does not reasonably provide enablement for a method of treating any claimed tumor(e.g. brain tumor /central nervous system tumor) with any compound of formula I in combination with any recited antitumor compound/molecular targeted drug. 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 without undue experimentation. This is a scope of enablement rejection.
To be enabling, 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 (Fed. Cir. 1993). The determination that "undue experimentation" would have been needed to practice the claimed invention in full scope is not a single, simple factual determination.
As stated in the MPEP 2164.01(a), “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." In In re Wands, 8 USPQ2d 1400 (1988), factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have need described. They are:
(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.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. Keeping that in mind, the Wands factors are relevant to the instant application for the following reasons:
The Breadth of The Claims/ Nature of The Invention
The nature of the invention are drawn to method for treating a tumor with compound of Formula I in combination with additional compound having an antitumor effect. Instant claim 57 does not recite any tumor type. As such, the tumor in claims 57-63 are construed as any tumor/cancer which is extremely broad. Instant claim 64 recites narrow scope of malignant tumor. However, epithelial cancer is a broad category that includes many common cancers such as breast, lung, colon, and prostate. Cancer of secretory system, tumors of central nervous system and peripheral nervous system are directed to vast variety of tumor/cancer that have different etiology, different symptoms, different location, different treatment mechanism and targeted outcome, etc. Instant claimed compound of Formula I comprising vast variety of Ring A, X,Q, R groups and variables are extremely broad. The additional antitumor compound have different structures, different biological/pharmacological activity, different mechanism of action, etc. are also very broad. As such, the scope of instant claimed method of treating vast variety of tumors/cancers with combination genus of compound of Formula I and additional compound genus are extremely broad.
The State of the Prior Art and the Predictability or Lack Thereof in the Art
It’s common knowledge that tumor/cancer is a heterogeneous disease and there is no established compound/agent, or combination of antitumor agents that could be used for treating all tumor/cancer. Even well- known antitumor compound/ molecular targeting drug, e.g. cetuximab, an EGFR inhibitor, could only be used for treating certain cancer (e.g. colorectal cancer or squamous cell carcinoma), but not for treating brain cancer or any tumor of central nervous system due to blood-brain barrier. Except compound 1, instant claimed compound of Formula I comprising vast variety of moieties/variables have not been tested in any antitumor assay as disclosed by instant specification, thus are not fully established as antitumor agent for any specific tumor/cancer. Activity by in-vitro experiment does not necessarily translate into in-vitro efficacy in animals and/or humans. As such, instantly claimed method for treating tumor/cancer genus having different etiology/different symptoms with instantly claimed compound of Formula I genus in combination with vast variety of antitumor/molecular targeting drug genus 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 (e.g., cancer prevention) is generally considered an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
The Amount of Direction Present and Presence or Absence of Working Examples
The specification does not provide sufficient guidance for a skilled artisan to practice the claimed method of treatment in its full scope. Instant specification only disclosed SHP2 inhibition activity of seven species of compound of Formula I ( compound 1-7, See Table 2). Instant specification does NOT disclose antitumor activity of the seven compound species except the elected compound 1. Instant specification does not disclose biological activity (SHP2 inhibition and/or antitumor activity) of any other compound of Formula I. As such, the compound of Formula I genus is not fully established by instant specification as SHP2 inhibitor that might be associated with antitumor activity against instant claimed tumor/cancer. Instant specification disclosed in-vitro assay of combination of compound 1 with exemplary molecular-targeted drugs(See Examples 2-13). Instant specification disclosed in-vivo test of compound 1 in combination with cetuximab on colorectal cancer cell SW 837 (See Example 14). Instant specification does not disclose any combination of compound 1 in assay of tumor/cancer for central nervous system or peripheral nervous system. There is no working example or data in the specification to provide a nexus between those working in-vitro examples and treating tumor/cancer of central nervous system or peripheral nervous system.
The level of one of ordinary skill in the art
The level of skill required to make and/or use the instant invention would likely require many years of professional experience conducting research in the art (e.g., medicine, pharmaceutical science, biology, biochemistry, medicinal chemistry, and/or organic chemistry, etc.) as well as an advanced educational degree (e.g., M.D. and/or Ph.D.) commensurate in level with the advanced techniques involved in the preparation and/or use of the instant invention.
The quantity of experimentation needed
An unduly extensive amount of experimentation would be required for one of ordinary skill in the art to be able to practice instantly claimed method of treating vast variety of tumor/cancer in full scope.
Instantly claimed compound of Formula I comprise millions of compound species. Thus, an extensive amount of experiment would be necessary to fully establish compound of Formula I as SHP2 inhibitor for the antitumor effect on different subjects. Working examples would be needed to determine the therapeutically effective dose for different type of tumor/cancer with combination comprising different compound of Formula I and different antitumor agent. The therapeutically effective amount may vary depending on many factors, such as the structure, property(chemical, physical, toxicological, etc.), mechanism of action, efficacy of the agent, administration route, subjects being treated, the disease condition and intended treatment outcome, etc. The specific dosage may vary depending on the compound selected, the dosing regimen to be followed, administration route, the toxicological profile, etc. The combination therapy also vary depending on the ratio/amount of different agents respectively and the interaction between agents, Therefore, it would be a great burden for one of ordinary skill in the art to carry out undue experimentation to use the claimed invention for claimed method of treating vast variety of tumors/cancers with combination genus of compound of Formula I with additional compound genus in full scope.
Conclusion
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 with respect to the claimed extremely vast scope of compound of Formula I for treating vast variety of tumor with any compound of Formula I in combination with any additional antitumor agent in view of the analysis above pursuant to In re Wands. In other words, one skilled in the art could not practice the claimed invention in full scope without undue experimentation.
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.
Claims 57- 64 are rejected under 35 U.S.C. 112(b), 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 57 is directed to a method of treating a tumor comprising administering a compound of formula (I) or a tautomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, and “at least one additional compound having an antitumor effect, at least one tautomer thereof, at least one solvate thereof, or at least one pharmaceutically acceptable salt thereof, selected from the group consisting of molecular targeted drugs and cytotoxic drugs”.
Compound of Formula I comprises vast variety of variables, Ring A, X, Q, R groups, a, b, c, etc. Claim 57 recites limitation wherein R2 and R3 are independently selected from the group consisting of hydrogen and C1-4 alkyl ; R6 and R7 are independently selected from the group consisting of halogen, C1-4 alkyl, hydroxy C1- 4alkyl, and hydroxyl … and
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The definition of
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moiety wherein any two groups selected from the group consisting of R2, R3, R6, and R7 together form a one- to three-membered bridge group, especially wherein a is 0, 1 or 2, is confusing. An ordinary skilled in the art would not be appraised of the scope of compound of Formula I comprising bridging group formed by any two of R2, R3 R6 and R7 in combination with ring moiety formed by R4 and R5, or R4 and R7 or R5 and R7 which is further complicated by different a variable.
The limitation of at least one additional compound having an antitumor effect selected from the group consisting of molecular targeted drugs and cytotoxic drugs is indefinite. The transitional phrase “consisting of” is close-ended. However, molecular targeted drugs and cytotoxic drugs are drug genus comprising vast variety of drugs and open-ended. The term “molecular targeted drugs” is an omnibus term and it’ s not clear what is the scope of “molecular targeted drugs”. Instant specification only disclose exemplary “molecular targeted drugs” , e.g. anthracycline antibiotics, alkaloid, anti-metabolite, anti-microtubule agent, etc. (See page 6-7, item 5, 6) without clear definition of what molecule are targeted by the “molecular targeted drugs”. Please note not all anthracycline antibiotics, alkaloid, anti-metabolite, anti-microtubule agent have antitumor effect. A person of ordinary skilled in the art would not be appraised of the scope of instant claimed at least one additional compound having an antitumor effect consisting of “molecular targeted drugs” and cytotoxic drugs, or at least one tautomer thereof, at least one solvate thereof, or at least one pharmaceutically acceptable salt thereof.
Claims 58-64 are rejected due to dependency on claim 57.
Claims 61 and 62 recite limitation wherein the at least one additional compound having an antitumor effect, selected from the group consisting of … an alkylating agent, an anthracycline antibiotic, an alkaloid, an anti-metabolite, an anti-microtubule agent, a platinum-containing drug, a proteasome inhibitor, and a thalidomide analog drug. The transitional phrase “consisting of” is close-ended. However, an alkylating agent, an anthracycline antibiotic, an alkaloid, an anti-metabolite, an anti-microtubule agent, a platinum-containing drug, a proteasome inhibitor, etc. are drug genus comprising vast variety of drugs and open-ended. A person of ordinary skilled in the art would not be appraised of the scope of instant claimed at least one additional compound having an antitumor effect.
Claim 64 recites “the malignant tumor is selected from the group consisting of epithelial cancer (respiratory cancer, gastrointestinal cancer, genital cancer, cancer of the secretory system, breast cancer, etc.), mesothelioma, sarcoma, hematopoietic tumor, tumors of the central nervous system, retinoblastoma, and tumors of the peripheral nervous system” . The transitional phrase “consisting of” is close-ended. However, epithelial cancer, cancer of the secretory system, tumors of the central nervous system, and tumors of the peripheral nervous system are cancer genus that are open-ended. Epithelial cancers, also known as carcinomas, are broad category that include many common cancers such as breast, lung, colon, and prostate cancer. The phrase ‘etc.” following exemplary epithelial cancer renders the claim indefinite because the claim includes elements not actually disclosed, thereby rendering the scope of the claim unascertainable. "Secretory system" is not a single medical term, instead, it refers to various organs that secrete substances, thus "cancer of the secretory system" could mean several types of cancer, such as salivary gland cancer, pituitary tumors, or even cancers that involve secretory proteins. It’s not clear what type of cancer is encompassed by instantly claimed epithelial cancers , cancer of the secretory system and tumors of the peripheral nervous system.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 57- 62 and 64 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Shimamura et al. (WO 2020/022323 A1, Applicant’s IDS dated 01/03/2023, published on January 30, 2020, family member of US 12037345 B2).
The applied reference has NO common joint inventor with the instant application, As such, the publication would be treated as prior art under AIA 35 U.S.C. 102(a)(1).
The applied reference has a common applicant/assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Shimamura disclosed pyrimidinone compound of Formula I as Src homology region 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2) inhibitor and method for prophylaxis or treatment of a disease or condition mediated by SHP2 (e.g. cancer) with aforementioned pyrimidinone compound (See abstract, [0012]-[0013], claims 1-17 ). It’s noted compound of Formula I disclosed by Shimamura has the same general formula as instant claimed compound of Formula I recited in claim 57 and similar definition of Ring A, X, Q, R groups and other moieties. Please refer to Shimamura reference for the complete list of Ring A, X, Q, R groups and other moieties
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Shimamura disclosed compound species that are encompassed by or very similar to instant claimed compound of Formula I, including instant elected compound species (See [0022], Examples 1-100, Table 10;). Shimamura explicitly teaches compound 93 which is instant elected compound species(See [0817], page 236, Table 10)(which reads on instant claims 59-60).
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Shimamura disclosed the disease or condition mediated by SHP2 include malignant tumors (See [0255]-[0256] )(which read on instant claim 57). Shimamura disclosed exemplary malignant cancer, e.g. breast cancer, osteosarcoma, soft-tissue sarcoma, chronic myeloproliferative disease, malignant lymphoma, multiple myeloma, brain tumor, mesothelioma, and the like (which reads on instant claim 64).
Shimamura collectively teaches method of treating disease/ condition mediated by SHP2 (e.g. malignant tumor, cancer) with pyrimidinone compound of Formula I as SHP2 inhibitor, including instant elected compound species. A skilled artisan would have known combination therapy comprising additional antitumor compound (e.g. alkylating agent, cisplatin/platinum-containing drug, etc.) is a common practice in cancer treatment. As such, Shimamura anticipates instant claimed invention.
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 non-obviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 57-64 are rejected under 35 U.S.C. 103 as being unpatentable over Shimamura et al. (WO 2020/022323 A1, Applicant’s IDS dated 01/03/2023, published on January 30, 2020, family member of US 12037345 B2), in view of Yuan et al. (J. Med. Chem. 2020, 63, 11368−11396, Recent Advances of SHP2 Inhibitors in Cancer Therapy: Current Development and Clinical Application, Applicant’s IDS dated 01/03/2023).
The collective teachings of Shimamura is elaborated in preceding 102 rejection and applied as before. Shimamura collectively teaches method of treating disease/ condition mediated by SHP2 (e.g. malignant tumor, cancer) with pyrimidinone compound of Formula I as SHP2 inhibitor, including instant elected compound species.
Shimamura is silent about combination with specific additional antitumor agent as recited in instant claim 63.
Yuan reviews the physiological and biological functions of SHP2 and development of SHP2 allosteric inhibitors in cancer therapy and clinical application (See full article). Yuan teaches SHP2 (Src homology-2 domain-containing protein tyrosine phosphatase-2) serves as an important hub to connect several intracellular oncogenic signaling pathways, such as Jak/STAT, PI3K/AKT, RAS/Raf/MAPK, and PD-1/PD-L1 pathways (See abstract, page 11368-11375). Yuan teaches variety of SHP2 inhibitor, Type I SHP2 (e.g. JAB-3068, TNO155, RMC-4630, and RLY-1971) (See p.11375, Figures 9-18), and Type 2 SHP2 inhibitor (p 11381, Figure 19-26). It’s noted compound 56- 59 in Figure 21 is very similar to instant claimed pyrimidinone compound of Formula I.
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Yuan teaches SHP2 inhibitors under clinical trials and combination therapy comprising SHP2 and other antitumor agent: “Because of the important role of SHP2 in regulating the reactivation of the RAS/Raf/ERK/MAPK pathway in cancers, the combination of allosteric SHP2 inhibitors with other
targeted therapy on this pathway has been investigated. In the preclinical studies, combination
therapies were shown to be more effective than a single agent and could overcome resistance to a single agent. Examples included the combination of SHP099 with MEK inhibitors, ALK inhibitors and ERK inhibitors. Combination of MEK inhibitors and 46 (SHP099) was shown to be especially effective in KRAS mutant tumors that acquired KRAS signaling caused by losing negative feedback inhibition
due to SHP2 activation…” (See page 11388, right column). Yuan further teaches variety of study wherein SHP2 inhibitors combine with specific antitumor agent, e.g. MEK inhibitor cobimetinib, spartalizumab (a PD-1 antibody) or ribociclib (a CDK inhibitor), Dabrafenib/BRAF, LTT462/ERK, trametinib/MEK,
LXH254/RAF, spartalizumab/PD-1) for advanced/metastatic BRAF V600 colorectal cancer, etc. (See page 11389, left column)(which reads on the antitumor agent of instant claim 63).
Combination therapy comprising additional antitumor compound is a common practice in cancer treatment as illustrated by Yuan. It would have been obvious for one of ordinary skilled in the art before the effective filing date of instant application to further explore combination therapy of pyrimidinone SHP2 inhibitor, compound of Formula I taught by Shimamura, with SHP2 combination therapy taught by Yuan, together with experimentation/optimization based on general knowledge of cancer treatment, and arrive at instantly claimed invention with reasonable expected success. At the time instant application was filed, it was already known that pyrimidinone compound of Formula I ( including instant elected compound species), could be made and used for treating disease/ condition mediated by SHP2 (e.g. malignant tumor, cancer) as taught by Shimamura. Yuan teaches the rationale of combination therapy comprising SHP2 inhibitor with other antitumor agent, e.g. MEK inhibitor, CDK inhibitors, etc. and exemplary combination comprising specific antitumor agent (e.g. dabrafenib).
A skilled artisan would be motivated to combine the teachings of Shimamura and Yuan because both teachings are directed to SHP2 inhibitors and Yuan teaches SHP2 inhibitor that’s similar to instant claimed pyrimidinone formula I, and rationale and examples of combination therapy comprising SHP2 inhibitor and other antitumor agent. Further exploration/optimization based on the combined teachings of prior art, together with general knowledge of cancer treatment would provide alternative combination therapy comprising compound of Formula I as SHP2 inhibitor and other antitumor agent that could overcome resistance to a single agent in treating certain malignant tumor/cancer (e.g. colorectal cancer).
One of ordinary skill in the art would have had reasonable expectation of success in producing instant claimed invention based on the combined teaching of prior art, together with general knowledge of cancer treatment. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 57-58 and 61-64 are rejected under 35 U.S.C. 103 as being unpatentable over Bagdanoff et. al. (WO2016/203404 A1, hereafter Bagdanoff ’404, Applicant’s IDS dated 01/03/2023 ), in view of Patani et. al. (Chem. Rev., 1996, 96, page 3147 – 3176, Applicant’s IDS dated 01/23/2024, Bioisosterism: A rational approach in drug design).
Bagdanoff ’404 teaches pyrimidinone compound of Formula I, Ia- Id, II as Src Homolgy-2 phosphatase (SHP2) inhibitor and method of treating disease /disorder associated with aberrant activity of SHP2(e.g. cancer) (See abstract, [0002], [0005], [0038]-[0039], claims 1-14).
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Bagdanoff ’404 teaches compound species, e.g. compound 31, compound 56, (See [00350], Table 1) that are very similar to instant claimed compound of Formula I. Compound 56 taught by Bagdanoff ’404 read on instant compound of Formula I, wherein X is N, Q is C, R1 is CH3, R2 and R3 is hydrogen, R4 and R5 together with Q forms a five-membered ring.
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Bagdanoff ’404 teaches variety of cancer associated with SHP2, e.g. colorectal cancer (See 0049]-[0061]). Bagdanoff ’404 teaches activity of pyrimidinone compound in SHP2 assay (See [00350]-[00356], Table 1) and use of pyrimidinone compound for treatment of disease/disorder mediated by SHP2 (e.g. breast cancer, squamous-cell carcinoma etc.) (See [0062]-[0064], claims 13-14).
Bagdanoff ’404 teaches pyrimidinone compound, may be administered simultaneously, sequentially or separately in combination with one or more anticancer compound (e.g. cisplatin, 5FU) that might offer synergistic activity (See [0065], [0066]).
Regarding the additional antitumor agent/molecular targeted drug recited in instant claims 61-63, Bagdanoff ’404 teaches pharmaceutical combination comprising pyrimidinone compound of Formula I with variety of antitumor agent, e.g. ALK inhibitors, MEK inhibitors, EGFR inhibitor, etc. (See [00140]-[00219]). Bagdanoff ’404 explicitly disclosed cetuximab, EGFR inhibitor (See [00153])(which reads on instant elected antitumor agent).
The difference of Bagdanoff ’404 compound and instant claimed compound of Formula I is the nitrogen containing moiety A. Bagdanoff ’404 teaches Ring A moiety containing oxygen, e.g. compound 56 comprising 2,3-dihydrobenzofuran. Bioisosteric modification from O to N based on Grimm’s Hydride Displacement Law is commonly known practice in the art of pharmaceutical industry as taught by Patani (See p. 3148-3149): “Atoms anywhere up to four places in the periodic system before an inert gas change their properties by uniting with one to four hydrogen atoms, in such a manner that the resulting combinations behave like pseudoatoms, which are similar to elements in the groups one to four places respectively, to their right”.
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Bagdanoff ’404 teaches R5b is a 5 to 6 member heteroaryl ring containing 1 to 4 heteroatoms selected from O, S and N, which further demonstrate the bioisosteric equivalency between O and N.
It would have been obvious to one of ordinary skill in the art before the effective filing date of instant application to explore more SHP2 inhibitors based on the collective teachings of Bagdanoff ’404 , together with general knowledge of structure similarity/ bioisosteric modification of SAR, and arrive at instant claimed invention with reasonable expectation of success. For example, compound 56 taught by Bagdanoff ’404 could have been modified by replacing O in 2,3-dihydrobenzofuran with NH and arrive at instant claimed Ring A moiety as five-membered nitrogen-containing heterocyclic ring.
According to M.P.E.P. § 2144.09, A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). Further exploration/optimization of pyrimidinone compound taught by Bagdanoff ’404, together with general knowledge of structure similarity/ bioisosteric modification of SAR would provide alternative pyrimidinone compound that are expected to have inhibitory activity on SHP2 for treating disease/disorder associated with SHP2 (e.g. breast cancer, colorectal cancer, etc.), alone or in combination therapy with additional anticancer agent (e.g. EGFR inhibitors).
One of ordinary skill in the art would have had reasonable expectation of success in producing instant claimed invention based on the collective teaching of prior art, together with general knowledge of structure similarity/ bioisosteric modification for SAR study and combination therapy in cancer treatment. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
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 57- 64 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. patent No. 12037345B2, in view of Yuan et al. (J. Med. Chem. 2020, 63, 11368−11396, Recent Advances of SHP2 Inhibitors in Cancer Therapy: Current Development and Clinical Application, Applicant’s IDS dated 01/03/2023).
Reference claims are directed to compound of Formula I or salt thereof that has the same core structure and similar substituents as instant claimed compounds, and method for treating disease or condition mediated by SHP2(e.g. cancer), comprising administering compound of Formula to a patient in need thereof.
Reference claim 10 recites compound species including instant elected compound species, 2- ((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptan-7-yl)-5-(3,4-dichloro-2- methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4- one (See Col. 399, line 40).
Reference claims 14 and 17 recite cancer type (e.g. breast cancer ) that read on instant claim 64.
Reference claims are silent about compound of Formula I in combination with additional antitumor agent. The collective teachings of Yuan is elaborated in preceding 103 rejection and applied as before. Combination therapy comprising additional antitumor compound is a common practice in cancer treatment as illustrated by Yuan. It would have been obvious for one of ordinary skilled in the art to further explore combination therapy of pyrimidinone SHP2 inhibitor, compound of Formula I taught by reference claims with SHP2 combination therapy taught by Yuan, together with experimentation/optimization based on general knowledge of cancer treatment, and arrive at instantly claimed invention with reasonable expected success. A skilled artisan would be motivated to further explore combination therapy of SHP2 inhibitors taught by reference claims because Yuan teaches SHP2 inhibitor that’s similar to reference pyrimidinone SHP inhibitor and rationale and examples of combination therapy comprising SHP2 inhibitor and other antitumor agent that could overcome resistance to a single agent in treating certain malignant tumor/cancer.
The instant application shares at least one common applicant with the reference application. Further, the instant application is not related to the reference application thus no 35 USC 121 shield exists. See MPEP 804.01.
Conclusion
No claims are allowed.
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/LIYUAN MOU/ Examiner, Art Unit 1628
/AMY L CLARK/Supervisory Patent Examiner, Art Unit 1628