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 .
Claims 1-10, submitted on 16 August 2024, represent all claims currently under consideration.
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.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
The effective filing date is 5 January 2021.
Information Disclosure Statement
Two Information Disclosure Statement (IDSs), submitted on 18 October 2023 and 6 October 2025, are acknowledged and have been considered.
Objection to the Specification
The Title is objected to because it contains the word “NOVEL”. All patentable inventions are necessarily novel, so such words should not be included in the title (See MPEP § 606). The word “NOVEL” has been deleted from the title. No further action is required on Applicant’s part.
The disclosure is objected to because of the following informalities: Several of the compounds of Table 1 have portions of the molecule cut off, making it difficult to interpret the complete structure of the compound. For example, Compound 3
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, 6
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and 36
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, among others are cut off by the table.
Appropriate correction is required.
Claim Objections
Claims 1 and 2 are objected to because of the following informalities: The claims are directed to “Compounds of formula (I), their pharmaceutically acceptable salts, enantiomers, and their diastereomers”. The claims should be directed towards a single compound of Formula (I), rather than multiple compounds. Appropriate correction is required.
Claim 1 is objected to because of the following informalities: The structure of Formula (I) is of poor quality and is difficult to interpret. Appropriate correction is required.
Claim 1 is objected to because of the following informalities: There is a comma missing between “-NRcCONraRb” and “-SO2NRaRb” in the descriptions of the substituents for variable R1, variables R3 and R4, and variables R6 and R7. Appropriate correction is required.
Claim 1 is objected to because of the following informalities: “Selected” is spelled incorrectly in the Markush group for variable W. Appropriate correction is required.
Claim 1 is objected to because of the following informalities: There is no comma separating “cycloalkyl” and “haloalkyl” in the Markush grouping for variables Ra through Rl. Appropriate correction is required.
Claim 4 is objected to because of the following informalities: The Claim reads “independently selected form” when it should read “independently selected from”. Appropriate correction is required.
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 9 and 10 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the treatment of cancers associated with autotaxins, does not reasonably provide enablement for the treatment of all forms of cancer, nor does it enable the prevention of cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims. Consideration of the relevant factors sufficient to establish a prima facie case for lack of enablement is set forth below:
The nature of the invention and breadth of the claims:
The claims are directed towards a method of treating and prevention of diseases including cancer, comprising administering to a patient in need a therapeutically effective amount of a compound of Claim 1. The compounds of Claim 1 are spirocyclic inhibitors of autotaxin which are useful for the treatment of conditions caused by autotaxin activation or increased concentration of lysophosphatidic acid. Thus, the claims are directed to a method which can be used to treat or prevent all forms of cancer using the compounds of the invention to inhibit autotaxin activity.
The state of the prior art and the predictability or unpredictability of the art:
Zhang (Cells, 2021, 10, 939) provides a review of autotaxin in disease, including cancer. Autotaxin (ATX) is a secreted glycoprotein and functions as a key enzyme to produce extracellular lysophosphatidic acid (LPA). LPA interacts with GPCRs to activate various signal transduction pathways, and this signaling axis plays an important role in pathological processes such as embryogenesis, obesity, and inflammation. ATX is one of the top 40 most unregulated genes in metastatic cancer, and the ATX-LPA axis is involved in the development of different types of cancer, such as colorectal cancer, ovarian cancer, breast cancer, and glioblastoma. ATX and LPA in the tumor microenvironment not only promote cell proliferation, migration, and survival, but also increase the expression of inflammation-related circuits, which results in poor outcomes for patients. Currently, ATX is regarded as a potential cancer therapeutic target (Abstract). It has been reported that ATX is highly expressed in many kinds of cancer, such as melanoma, glioblastoma, renal cancer, liver cancer, and hepatocarcinoma. The positive rate of ATX protein expression in hepatocellular carcinoma was 89% (34 of 38) while ATX in normal samples was 20% (5. Roles of the ATX-LPA Axis in Cancers). According to existing results, ATX is highly expressed in various cancer cells, and the ATX-LPA axis is of great significance in oncogenesis and cancer progression. The mechanism of ATX in cancer cells is still not fully clear and needs to be further clarified. Inhibitors of ATX may be used in the clinical treatment of cancer in the future (7. Future Works). However, not all cancers can be successfully treated in this manner, and there is currently no known treatment that can be used to treat all forms of cancer.
The prior art also does not support the prevention of cancer using any known small molecule. Hassanpour (Journal of Cancer Research and Practice, 4, 2017, 127-129) performed a review of the molecular causes of cancer. Cancer in a broader sense refers to more than 277 different types of cancer disease. Several gene mutations are involved in cancer pathogenesis, leading to abnormal cell proliferation. Genetic disorders caused by heritance or inheritance factors have a pivotal role in the increase of cell growth (Abstract). Cancer occurs by a series of successive mutations in genes so that these mutations change cell functions. Chemical compounds have an obvious role of forming gene mutations and cancer cells. Viruses, bacteria and radiation are other carcinogenesis factors, comprising about 7% of all cancers. Lack of tumor suppressor genes triggers uncontrolled cell division (Introduction, throughout). Genetic changes that led to oncogene generation and genetic disorders include chromosomal translocation (gene Bccr and oncogene Abl in chronic blood cancer), point mutation (Ras gene in colon cancer), deletion (Erb-B gene in breast cancer), amplification (N-myc in neuroblastoma) and insertion activation (C-myc in acute blood cancer). Mutation in the p53 gene leads to formation of an unusual protein that has a prominent role in disturbance of molecular processes related to p53. It has been reported that p53 abnormality occurs in 60% of cancer cases. BRG1 and BRM are known as tumor suppressors that manifest a pivotal role in 15-20% of lung cancer. Disabling of this complex disrupts cell growth. (Cancer from the molecular perspective). Many aspects of epigenetic causes of cancer remain unknown (Conclusion). Blackadar (World Journal of Clinical Oncology, 2016 February 10; 7(1): 54-86) further expands on this, by reviewing known environmental factors implicated in cancer. There is now sufficient evidence of carcinogenicity for humans for human T-cell lymphotrophic virus, HIV, hepatitis B and C virus, HPV, Epstein-Barr virus, and human herpes virus 9 according to the International Agency for Research on Cancer. (Abstract). HIV is associated with the development of Kaposi’s sarcoma (Page 63). The mechanism of how HIV causes cancer is not straightforward. Immunosuppression caused by HIV is a potent cofactor in KS and lymphomas. The IARC concluded in 2012 that HIV causes not only Kaposi sarcoma and non-Hodgkin’s lymphoma, but also Hodgkin’s lymphoma, and cancers of the cervix, anus, and conjunctiva (Page 63). Human papilloma virus 16 and 18 (HPV-16 and HPV-18) produce a number of proteins which have oncogenetic activities. These proteins induce instability by binding to the tumor suppressor protein p53, interfering with its normal function and inducing its degradation. Initial studies with HPV focused on identification of the cause of cervical cancer. Further studies have shown that mucosotropic HPV types also cause cancer of the vulva, vagina, penis, oropharynx, oral cavity, and tonsil (Page 64, Human Papillomavirus, throughout). Hepatitis C virus (HCV) has been implicated in the development of hepatocellular carcinoma. HCV induced HCC evolves through a progression of chronic hepatitis, to cirrhosis, to HCC which generally requires 20-30 years or longer to develop. Around 40% of patients with chronic HCV develop cirrhosis after 30 years. While HCC develops mostly among cirrhotics, it also develops at low rates among patients devoid of cirrhosis, which is interpreted as evidence that the virus may possess some directly carcinogenic effects (Page 65, Hepatitis C Virus, Throughout). H. pylorus has been estimated to cause around 2/3 of the cases of gastric cancer, and is estimated to cause 5.5% of the world cancer burden. The global burden of cancer due to infectious agents has been estimated to be 17.8% (Conclusion, Page 71). The American Cancer Society (cancer.org, Can Acute Lymphocytic Leukemia Be Prevented?, https://web.archive.org/web/20241209175137/https://www.cancer.org/cancer/types/acute-lymphocytic-leukemia/causes-risks-prevention/prevention.html, Last updated 17 October 2018) states that it is not clear what causes most cases of acute lymphocytic leukemia, and that since most people with ALL don’t have risk factors that can be changed, there is no known way to prevent most cases of ALL. Avoiding exposure to known cancer-causing chemicals might lower the risk, but most experts agree that exposure to workplace and environmental chemicals seems to account for only a small portion of leukemias. The American Cancer Society (cancer.org, Can Hodgkin Lymphoma be Prevented?, https://web.archive.org/web/20231211145704/https://www.cancer.org/cancer/types/hodgkin-lymphoma/causes-risks-prevention/prevention.html, Last updated 1 May 2018) states that few of the known risk factors for Hodgkin lymphoma can be changed, making it impossible to prevent most cases of the disease at this time. A major risk factor for HL is infection with the Epstein-Barr virus, which currently has no known preventative measures. In view of these teachings, the causes of cancer are heterogeneous, and often unpredictable, evidenced by the various infectious diseases associated with cancer, with no current preventative treatments available.
The relative skill of those in the art:
The artisan would generally have an advanced degree related to the treatment or study of various cancers; however, their high level of training and knowledge would not be sufficient to overcome the lack of understanding of how to use the claimed compounds to treat all forms of cancer, as not all forms of cancer are sensitive to inhibition or antagonism of autotaxin activity, nor is there any evidence in the current state of the art that any form of cancer can be prevented using small molecules.
The amount of direction or guidance presented and the presence or absence of working examples:
The specification demonstrates that the compounds of the invention are capable of inhibiting the activity of autotaxin in vitro (Table 2, Page 74) with varying efficacies. Thus, the specification enables the treatment of conditions which are associated with aberrant autotaxin activity or expression. However, the specification does not demonstrate the treatment of all forms of cancer, nor does the specification demonstrate the prevention of cancer.
The quantity of experimentation necessary:
Considering the state of the art as described above, in particular with regards to the lack of a panacea for the treatment of cancer due to the heterogenous nature of the disease, the lack of evidence in the art of any small molecule which can prevent cancer, and the high unpredictability of the art as evidenced therein, and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to practice the invention commensurate with the scope of the claims.
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.
Claim 1 is 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 1 is indefinite because there is no “or” or “and” before the final entry of the Markush groups for variables R1, R2, or R3. Claims 2-5 and 7-10 are similarly rejected as indefinite for depending upon an indefinite claim without resolving the underlying issue of indefiniteness.
Claim 4 is 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 4 is indefinite because there is no “or” or “and” before the final entry of the Markush group of the substituents for variables R6 and R7.
Claim 8 is 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. Regarding Claim 8, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 8 is 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. The metes and bounds of the “other suitable therapeutic agents”, and specifically, of “anti-inflammatory agents, antitumor agents, antifibrotic agents, autotaxin inhibitors, immunomodulators, and cardiovascular agents” are not defined within the claim, nor within the specification. This renders the metes and bounds of the claim as undefined, and therefore, indefinite.
Claim 9 is 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. The language “the compound as claimed in Claim 1 or its pharmaceutical composition is useful in the prevention” is unclear, and the Examiner is unsure of what is specifically being claimed. It is unclear if this claim is intended to be a methods claim, since it lacks the steps which specifically set out a defined method.
Claim 10 is 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. Regarding Claim 10, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 10 is 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 10 claims a “method of treating diseases fibrosis…”. It is unclear what is meant by the phrase “diseases fibrosis”. The Examiner is assuming this is intended to state “disease, wherein the disease is selected from…”.
Claim Rejections - 35 USC § 102
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 1, 3, 5, and 7-10 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Wrona (WO 2021/247893; Priority to 24 November 2020 and 3 June 2020).
Wrona discloses compounds useful in the treatment of neurological disorders (Abstract). Compound 128 (Page 10)
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, Compound 30 (Page 10)
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, 132 (Page 10)
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, 31 (Page 10)
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, 34 (Page 11)
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, and 134 (Page 11)
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each have variable R1 as substituted heteroaryl, W as -C(O), R2 as H, R3 as H, and R4 as substituted arylalkyl. Compounds 30, 31, and 134 have m or n as 1 and the other as 0. Compounds 128, 132 and 134 have both m and n as 1. Compounds 128 and 134 have X as -O-, Compound 31 has X as (CH2) with r as 2 (Forming a 6 membered ring), and the remaining compounds have X as CH2 with r as 1. Compounds 30 and 31 have Y as -O-, Compound 34 has Y as -C(O)-, with the remaining compounds have Y as -CH2-. Compound 34 has Z as -NH- with the remaining compounds having Z as CH2. The invention features a pharmaceutical composition comprising any of the foregoing compounds and a pharmaceutically acceptable excipient (Page 21, Lines 2-3). In an aspect, the invention features a method of treating a neurological disorder (e.g., frontotemporal dementia, chronic traumatic encephalopathy, ALS, Alzheimer’s disease, LATE, or frontotemporal lobar degeneration) in a subject in need thereof comprising administering an effective amount of any of the foregoing compounds or pharmaceutical compositions (Page 21, Lines 4-8). The compounds of the invention can be combined with one or more therapeutic agents. A compound of the invention can be used alone or in combination with other agents that treat neurological disorders or symptoms associated therewith, or in combination with other types of treatments to treat, prevent and/or reduce the risk of any neurological disorder (Page 47, Lines 23-30). Example 7 (Page 88) demonstrates that the compounds of the invention modulate TDP-43 aggregation, demonstrating that these compounds treat diseases mediated by TDP-43. Diseases such as CTE and Alzheimer’s diseases are considered chronic inflammatory conditions.
Claims 1 and 3 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ambarkhane (US 2012/0302540; Publication Date: 29 November 2012).
Ambarkhane discloses the intermediate
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which has variable R1 as methyl substituted with –(CRaRb)pNRaRb with p as 0, Ra as H, Rb as -COORj with Rj as C4 alkyl, W -C(O)-, R2 as H, R3 as H, R4 as alkyl substituted with (CH2)pORa with Ra as arylalkyl, one of m or n as 1 and the other as 0, X as C(O), Y as Nri with Ri as methyl, and R6 as aryl.
Claims 1, 2, 3, and 5 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Makovec (Journal of Medicinal Chemistry, 1996, 29, 135-142).
Scheme 1 (Page 135) discloses several anticipatory compounds.
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has variable R1 as aryl substituted with halogen, W as -C(O)-, R2 as H, R3 as H and R4 as alkyl substituted with -C(O)NReRf with Re as H and Rf as –(CRjRk)tCOORj with Rj, Rk, and Rj each as H and t as 1, m and n as 1, and X, Y, and Z each as CH2.
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has variable R1 as aryl substituted with halogen, W as -C(O)-, R2 as H, R3 as H and R4 as alkyl substituted with -C(O)NReRf with Re as methyl and Rf as –(CRjRk)tCOORj with Rj, Rk, and Rj each as H and t as 1, m and n as 1, and X, Y, and Z each as CH2.
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has variable R1 as aryl substituted with halogen, W as -C(O)-, R2 as H, R3 as H and R4 as alkyl substituted with -C(O)NReRf with Re as H and Rf as –(CRjRk)tCOORj with Rj, Rk, and Rj each as H and t as 2, m and n as 1, and X, Y, and Z each as CH2.
Claims 1-3, 7, 9 and 10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Makovec (WO 93/21172; Publication Date: 28 October 1993).
Makovec discloses compounds as gastrin or cholecystokinin antagonists (Abstract). One disclosed compound is
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,which has variable R1 as phenyl substituted with CF3, W as -C(O), R2 as H, R3 as H, R4 as -C(O)NReRf with Re as H and Rf as –(CRjRk)tNRjRk with Rj and Rk as H, t as 2, and Rj and Rk as methyl, m and an as 1, and X, Y, and Z each as CH2. These compounds are useful in the treatment of diseases such as colitis, biliary dyskinesia, pancreatitis, gastritis, peptic ulcers, and certain forms of intestinal tumors which are sustained by gastrin or polypeptide hormones related thereto (Page 5). Claim 5 claims a pharmaceutical preparation comprising a compound of the invention or a pharmaceutically acceptable salt thereof. Claim 9 claims a pharmaceutical preparation for use in treatment of conditions such as colitis and pancreatitis, which are inflammatory conditions.
Claims 1, 2, 7, and 9 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by McDonald (WO 93/14066; Publication Date: 22 July 1993).
McDonald discloses amino acid derivatives with anticholecytsokinin activity (Abstract). One compound is
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, which has variable R1 as aryl, W as -S(O)2, R2 as H, R3 as H, R4 as alkyl substituted with -COORe with Re as H, m and n as 1, and X, Y, and Z each as CH2. For oral administration, the compounds of the invention will be generally provided in the form of tablets or capsules. Tablets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients (Page 17).
Claims 1-3, 7, 9, and 10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Makovec (WO 92/10479; Publication Date: 25 June 1992).
Makovec discloses compounds with anti-gastrin activity (Abstract). One compound disclosed is
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which has variable R1 as aryl substituted with halo, W as -C(O)-, R2 as H, R3 as H and R4 as alkyl substituted with -COORe with Re as H, m and n as 1, and X, Y, and Z each as CH2. These compounds are useful for the treatment of diseases such as gastro-duodenitis (an inflammatory condition) (Page 4), colitis, and pancreatitis (Page 5). Claim 3 claims a pharmaceutical preparation including a compound of the invention. Claims 5, 6, 7, and 8 claims methods of treatment of various inflammatory conditions and tumorous disorders sustained by gastrin and other bioactive polypeptides.
Claims 1-3, and 7-10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Torisu (WO 2006/006490; Publication Date: 16 January 2006).
Torisu discloses compounds that are useful for the prevention and/or treatment of thrombotic diseases attributable to the activation of the blood coagulation mechanism, such as thrombosis/embolism accompanying cardiovascular disease, thrombosis/embolism accompanying cerebrovascular disease, and thrombosis/embolism accompanying venous vascular diseases (Abstract). One compound disclosed is
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which has variable R1 as heteroaryl substituted with halo, W as -C(O)-, R2 as H, R3 as H and R4 as aryl, m and n as 1, and Z as Nri with Ri as heteroaryl. Another disclosed compound is
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which has variable R1 as aryl substituted with halo, W as S(O)2, R2 as H, R3 and R4 as H, m and n as 1, and Z as Nri with Ri as heteroaryl. The compounds disclosed are FXa inhibitors and are useful as anticoagulants (Paragraph 0005). The compound of the invention can be administered as a combination agent in combination with other drugs for improved absorption, reduced dosage, or to reduce the side effects of the compound (Paragraph 0179). For example, blood pressure lowering drugs, hyperlipidemia drugs, antiplatelet drugs, anticoagulants, thrombolytic drugs, vasodilators, brain function improvement drugs, antidementia drugs, antitumor drugs, hypoglycemic drugs, and anti-obesity drugs can be administered with the compound of the invention (Paragraph 0182). Claim 24 claims a pharmaceutical composition of a compound of the invention. Claim 30 claims a method of treating a disease mediated by blood coagulation factor Xa comprising administering a therapeutically effective amount of a compound of the invention.
Claims 1-3 and 9 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gupta (Molecular Informatics, Volume 14, Issue 5, 1995, 437-443).
Gupta discloses compounds which are useful as CCK antagonists which are useful for the treatment of inflammatory conditions such as pancreatitis. Table 2 (Page 439) discloses several anticipatory compounds.
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has variable R1 as aryl substituted with halo, W as -C(O)-, R2 as H, R3 as H and R4 as alkyl substituted with -COORe with Re as H, m and n as 1, and X, Y, and Z each as CH2.
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298
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has variable R1 as aryl substituted with alkyl, W as -C(O)-, R2 as H, R3 as H and R4 as alkyl substituted with -COORe with Re as H, m and n as 1, and X, Y, and Z each as CH2.
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has variable R1 as aryl substituted with alkyl, W as -C(O)-, R2 as H, R3 as H and R4 as alkyl substituted with -COORe with Re as H, m and n as 1, and X, Y, and Z each as CH2.
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has variable R1 as aryl substituted with alkoxy, W as -C(O)-, R2 as H, R3 as H and R4 as alkyl substituted with -COORe with Re as H, m and n as 1, and X, Y, and Z each as CH2.
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has variable R1 as aryl substituted with cyano, W as -C(O)-, R2 as H, R3 as H and R4 as alkyl substituted with -COORe with Re as H, m and n as 1, and X, Y, and Z each as CH2.
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has variable R1 as aryl substituted with haloalkyl, W as -C(O)-, R2 as H, R3 as H and R4 as alkyl substituted with -COORe with Re as H, m and n as 1, and X, Y, and Z each as CH2.
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has variable R1 as aryl, W as -C(O)-, R2 as H, R3 as H and R4 as alkyl substituted with -COORe with Re as H, m and n as 1, and X, Y, and Z each as CH2.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-10 are rejected under 35 U.S.C. 103 as being unpatentable over Babiss (WO 2015/154023; Publication Date: 8 October 2015) in view of Thornber (Chemical Society Reviews, 4, 1979).
Babiss (See IDS, 18 October 2023) discloses compounds which are inhibitors of autotaxin, and their use in methods of treatment of conditions such as cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis, and cholestatic pruritus (Abstract). Compounds of the invention include Example 1 (Page 21)
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(Page 21), Example 2 (Page 24)
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, Example 3 (Page 24)
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, Example 6 (Page 25)
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, Example 7 (Page 26)
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, Example 10 (Page 27)
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, Example 12 (Page 28)
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, Example 14 (Page 29)
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, Example 25 (Page 33)
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, Example 52 (Page 50)
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, Example 58 (Page 56)
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, Example 95 (Page 85)
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, and Example 131 (Page 103)
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. These are just a selection of the many compounds disclosed which meet the limitations of the compounds of the examined application, but contain a nitrogen in the spirocyclic ring which is not found in the compounds of the examined application. Compounds 1, 6, 7, 10, 12, 14, 25, 52, 58, 131 each had IC50 values against autotaxin activity between 0 and 500 nM, providing a rationale for selecting these compounds for modification and giving a reasonable expectation of success as these compounds are biologically active. Compound 3 and 95 have between 500 and 1000 nM IC50 values and would provide a rationale for selection as this value demonstrates biological activity (Table 1, Page 234). The present invention includes pharmaceutical compositions comprising a compound of the invention, which is formulated with or without one or more pharmaceutically acceptable carriers. The compounds can also be included in compositions in combination with one or more other therapeutically active compounds (Page 235). Compounds of the present invention inhibit the activity of autotaxin in animals and are useful in the treatment of various diseases such as cancer, lymphocyte homing and inflammation, neuropathic pain, fibrotic diseases, thrombosis, and cholestatic pruritus (Page 237). The invention includes methods of treating these conditions using compounds of the invention (Pages 237-238). In some embodiments, the method further comprises administering at least one additional active agent. In some embodiments, the invention includes a method of treating cancer comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of the invention wherein at least one additional active anti-cancer agent is used as part of the method (Page 239).
Babiss does not teach compounds wherein the spirocyclic moiety has carbon rather than nitrogen in the analogous position of the compounds of the examined application.
Thornber teaches the concept of bioisosterism, which describes the similarity of molecules or ions which have the same number of atoms or valence electrons. Bioisosteres are groups or molecules which have chemical and physical similarities producing broadly similar biological properties (Page 563). Table 1 lists the classical isosteres, which includes ring equivalents. Classical isosteric ring equivalents include -O-, -S-, -CH2-, and -NH- (Table 1, Page 564). These groups are considered ring equivalents because of the similar electronic properties which they possess.
Babiss and Thornber are considered analogous to the claimed invention as all are involved in the design and development of therapeutics. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to modify the autotaxin antagonists of Babiss by replacing the ring nitrogen with carbon as Thornber teaches these are classical isosteres, and the resulting compounds would not be expected to have significantly different chemical properties. These compounds are prima facie obvious over the invention due to the close chemical structure; this substitution would not be expected to significantly alter the properties of the parent compound (See MPEP § 2144.09 I). The artisan would be motivated, and have a reasonable expectation of success, in modifying these compounds as they are shown to be potent antagonists of autotaxin.
Claims 1-10 are rejected under 35 U.S.C. 103 as being unpatentable over Sundy (WO 2017/152062; Publication Date: 8 September 2017) in view of Thornber (Chemical Society Reviews, 4, 1979).
Sundy (See IDS, 18 October 2023) discloses pharmaceutical comprising an autotaxin inhibitor and an additional therapeutic agent such as anti-fibrotics, anti-inflammatory agents, anti-cancer agents, and cardiovascular agents (Abstract). The present invention provides a pharmaceutical composition including a therapeutically effective amount of an autotaxin inhibitor of formula I
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wherein X1 and X2 are independently selected from C1-C2 alkyl, -C(O)-, NR3 or O; X3 is selected from C1-C2 alkyl, -C(O)-, NR3, O, or CR10R11; m and n are independently selected from 0, 1, or 2 (Page 3). R1 is selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, all of which can be optionally substituted. R2 is selected from alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, all of which can be optionally substituted (Page 19-20). In some embodiments, the compound is of Formula Ih
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(Page 36). In some embodiments, the compound is of Formula Ik
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(Page 36). In some embodiments, the compound is of Formula Ip
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(Page 37). In some embodiments, the compound is of Formula Iq
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(Page 37). In some embodiments, the compound is of Formula Is
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(Page 38). In some embodiments, the compound is of Formula Iv
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(Page 38). In some embodiments, the compound is of Formula Iw
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(Page 39). Specific compounds which are identical to those of Babiss (See previous rejection) are disclosed. The additional therapeutic agent used with the compound of formula I can be any suitable agent. For example, the additional therapeutic agent can be an anti-fibrotic agent, an oncology agent, an ASK-1 inhibitor, a cardiovascular agent, a SYK inhibitor, and others (Paragraph 0136, Page 62). In some embodiments, a method for treating a fibrotic disease is provided comprising administering to the human a therapeutically effective amount of a compound disclosed herein in combination with a therapeutically effective amount of one or more additional therapeutic agents (Paragraph 0139).
Sundy does not teach compounds wherein the spirocyclic moiety has carbon rather than nitrogen in the analogous position of the compounds of the examined application.
The teachings of Thornber are described previously and are fully incorporated into this rejection.
Sundy and Thornber are considered analogous to the claimed invention as all are involved in the design and development of therapeutics. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to modify the autotaxin antagonists of Sundy by replacing the ring nitrogen with carbon as Thornber teaches these are classical isosteres, and the resulting compounds would not be expected to have significantly different chemical properties. These compounds are prima facie obvious over the invention due to the close chemical structure; this substitution would not be expected to significantly alter the properties of the parent compound (See MPEP § 2144.09 I). The artisan would be motivated, and have a reasonable expectation of success, in modifying these compounds as they are shown to be potent antagonists of autotaxin.
Conclusion
Claims 1-10 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHILLIP MATTHEW RZECZYCKI whose telephone number is (703)756-5326. The examiner can normally be reached Monday Thru Friday 730AM-5PM EST.
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/P.M.R./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625