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 Group I (Claims 1-8 and 12-16) as well as compound 1
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in the reply filed on 6 August 2026 is acknowledged. The traversal is on the ground(s) that Applicant provides direct experimental evidence refuting the prediction on which the rejection of unity depends. Applicant compared compounds of the invention with STF22
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which differs from the compound of Hawley cited in the restriction requirement by the linker (methylene versus ethylene). The data provided in the specification shows that there is significantly improved ENPP1 inhibitory activity when the ring -CH= is replaced with an N, which is an unexpected result given the similar electronic properties. The Examiner finds these arguments to be persuasive and the restriction and election requirement are each withdrawn.
Claims 1-8 and 10-17, submitted on 19 July 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 21 January 2022.
Information Disclosure Statement
Five Information Disclosure Statements (IDSs), submitted on 19 July 2024, 27 August 2024, 2 July 2025, 3 December 2025, and 13 August 2026, are acknowledged and have been considered.
Specification
The spacing of the lines of the specification is such as to make reading difficult. New application papers with lines 1 1/2 or double spaced (see 37 CFR 1.52(b)(2)) on good quality paper are required.
Claim Objections
Claim 7 is objected to because of the following informalities: There should be an “or” or “and” prior to the final compound in the table. 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 10, 11, and 17 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 ENPP1-mediated diseases such as cancer, does not reasonably provide enablement for the prevention of these conditions, including 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 use 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 drawn to methods for treating and/or preventing a disease or disorder mediated by ENPP1, and this includes various types of cancers, by using a compound of the invention. The compounds of the invention are inhibitors of ENPP1. Thus, the claim is towards a method which can be used to prevent cancer using inhibitors of ENPP1. The specification defines prevention as “the administration of one or more pharmaceutical substances to individuals with a predisposition to the disease, in order to prevent them from developing the disease” (Page 33, Lines 20-24).
The state of the prior art and the predictability or unpredictability of the art:
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 how the use of the claimed compounds would prevent the development of all cancers as there is no current evidence in the state of medical technology that cancer can be prevented utilizing a small molecule.
The amount of direction or guidance presented and the presence or absence of working examples:
Table 1 (Page 60) demonstrates that the compounds of the invention are potent inhibitors of ENPP1 kinase, and thus, are capable of treating cancers and other diseases or disorders which are mediated by ENPP1. However, there is no data provided which demonstrates that these compounds can prevent the development of cancer.
The quantity of experimentation necessary:
Considering the state of the art as described above, in particular with regards to the heterogeneity underlying the causes of cancer and the current lack of preventative therapeutics, 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.
Claims 10, 11, and 17 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. The claims are indefinite as they are directed towards a method for treating or preventing ENPP1-mediated diseases or disorders (plural). It is unclear from this limitation if the patient must be suffering from multiple ENPP1-mediated diseases or disorders for this method to be practiced, or if the patient is suffering from only one disease/disorder. The Examiner suggests amending the claims to read “an ENPP1-mediated disease or disorder” to overcome this rejection, and amending Claims 11 and 17 to indicate that the method is for the treatment of a singular disease/disorder.
Claims 2 and 13-14 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. The claims are indefinite because there is no “or” or “and” present prior to the different options for the
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group in each of the claims, causing indefiniteness if the options for these groups are required to be used with the options present for the bicyclic ring system.
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 claim is indefinite due to the phrasing “comprising one or more selected from the compound of formula (I) or formula (I-A)”. The Examiner believes that the word “compound” should be present to make the limitation read “comprising one or more compound selected from the compound of formula (I) or formula (I-A).
Claims 10, 11, and 17 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. The claims are indefinite due to the limitation of “including administering”. It is unclear if the limitations which follow “including” are necessary parts of the invention or merely representative. The Examiner suggests replacing “including” with “comprising”, “consisting of”, or “consisting essentially of” to overcome this rejection. Claims 11 and 17 are similarly rejected as indefinite for depending upon an indefinite claim without resolving the underlying issue of indefiniteness.
Claims 10, 11, and 17 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. The claims are indefinite due to the language “administering a therapeutically effective amount of one or more selected from the compound of formula (I) or formula (I-A)”. The Examiner believes that the word “compound” should be present to make the limitation read “comprising one or more compound selected from the compound of formula (I) or formula (I-A). Claims 11 and 17 are similarly rejected as indefinite for depending upon an indefinite claim without resolving the underlying issue of indefiniteness.
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 1-8 and 10-17 are rejected under 35 U.S.C. 103 as being unpatentable over Li (WO 2020/160333; Publication Date: 6 August 2020) in view of Gallatin (WO 2019/046778; Publication Date: 7 March 2019).
Determining the Scope and Contents of the Prior Art:
Li (See IDS, 3 December 2025) discloses compounds, compositions, and methods for the inhibition of ENPP1. Also provided are pharmaceutical compositions and methods for treating cancer. Aspects of the methods include administering to a subject a therapeutically effective amount of an ENPP1 inhibitor to treat the subject for cancer (Abstract). The subject ENPP1 inhibitor compounds include a core structure based on an aryl or heteroaryl ring system, e.g., a quinazoline or quinoline group, which his linked to a hydrophilic head group (Paragraph 0090). The term “hydrophilic head group” refers to a group linked to the core aryl or heteroaryl ring system and well solvated in aqueous environments. The hydrophilic head group can impart improved water solubility and reduced cell permeability upon the molecule to which it is attached. In some cases, the hydrophilic head group is included in a prodrug form and as such includes a promoiety that can be removed in vivo (Paragraph 0091). In certain cases, the hydrophilic head group is a phosphorous containing group (Paragraph 0092).Compounds of the invention are of formula
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wherein
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(Paragraph 0094). The hydrophilic head group X1 or prodrug form thereof is selected from:
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(Paragraph 00188). Table 1 (Page 46) lists several compounds of the invention, such as
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,
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, and
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. These compounds and those similar to these have inhibitory activity against ENPP1 of below 100 nM (Rable 4, Page 126). Aspects o the methods include administering to a subject with cancer a therapeutically effective amount of an ENPP1 inhibitor to treat the subject for cancer. In certain embodiments, the cancer is selected from adrenal, liver, kidney, bladder, breast, colon, gastric, ovarian, cervical, uterine, esophaeal, colorectal, prostate, pancreatic, lung (both small cell and non-small cell), thyroid, carcinomas, sarcomas, glioblastomas, melanoma, and head and neck tumors. In some embodiments, the cancer is lymphoma (Paragraph 00230). The herein-discussed compounds can be formulated using any convenient excipients, reagents, and methods (Paragraph 00270).
Gallatin discloses methods and compounds of augmenting and enhancing the production of type IFNs in vivo. In some embodiments, the compounds disclosed herein are ENPP1 inhibitors, pharmaceutical compositions, and methods for the treatment of cancer or a viral infection (Abstract). Disclosed herein are compounds of Formula (X)
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wherein
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(Paragraph 0004). In some embodiments,
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is
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(Paragraph 0216). Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient (Paragraph 0010). Also disclosed herein is a method of treating cancer in a subject comprising administering a compound disclosed herein (Paragraph 0011). Also disclosed herein is a method of treating an infection in a subject in need thereof comprising administering a compound disclosed herein (Paragraph 0012). Table 1 (Page 82) lists specific embodiments of the invention, including Compound 73
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, Compound 102
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, Compound 103
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, Compound 321
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, Compound 330
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, Compound 346
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, Compound 349
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, Compound 352
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, Compound 393
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, and Compound 411
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. These compounds displayed varying efficacy in inhibiting ENPP1, with some having a Ki against cGAMP of less than 100 nm (Table 3, Paragraph 0639). Claim 136 claims a method for treating a viral infection using compounds of the invention, wherein the virus is due to a herpesvirus such as HSV-1, HSV-2, VXV, human cytomegalovirus. Claim 140 claims treatment of a hepatitis virus. Claim 144 claims the treatment of a dengue fever virus, yellow fever virus, ebola virus, Marbug virus, Venezuelan encephalitis virus, or zika virus.
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
Li does not disclose that the ENPP1 inhibitors have analogous variables X1 through X4 as N, while Gallatin does not disclose that their ENPP1 inhibitory compounds have a phosphate as the hydrophilic head group.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The artisan would have extensive training as a medicinal or pharmaceutical chemist, with further experience in structure based drug design and determining the relationship between the placement of functional groups within compounds and how this impacts ADME properties of a compound when administered.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
Li and Gallatin are considered analogous to the claimed invention as all are involved in the use of fused heteroaromatic ring systems for the inhibition of ENPP1 and the treatment of conditions mediated by this enzyme. 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 combine the heteroaromatic scaffolds provided by Gallatin with the phosphate groups disclosed by Li as the hydrophilic head of the compounds, arriving at the compounds of the examined application. The combination of these two teachings to arrive at the claimed invention is prima facie obvious use of a known technique to a known product ready for improvement to yield predictable results (See MPEP § 2143 I (C)). Li states that the hydrophilic head group can impart improved water solubility and reduced cell permeability upon the molecule to which it is attached. Thus, Li teaches that modification of this hydrophilic head group can be used to improve the physicochemical properties of these compounds. The compounds of Gallatin have a different hydrophilic head group, and the artisan would recognize that by modifying the compounds of Gallatin to include this group results in improved properties such as solubility, which will lead to enhanced delivery of the compound and improved therapeutic efficacy. The artisan would be motivated to modify these compounds as both Li and Gallatin have demonstrated that the compounds (cited above) are potent inhibitors of ENPP1. However, these compounds may not have favorable physicochemical properties, and by modifying this head group, solubility can be improved, resulting in a more effective treatment.
Regarding Claim 7, the compounds cited represent obvious variations of what is claimed, with these compounds differing by the exact location of the ring nitrogen, the length of the alkylene linker, or the inclusion of different phosphate esters which are disclosed by Li as being useful for imparting pro-drug functionality. The artisan would not expect these modifications to result compounds which differ significantly from what could be arrived at from the combined teachings of Li and Gallatin.
Conclusion
Claims 1-8 and 10-17 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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Andrew Kosar can be reached at 571-272-0913. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/P.M.R./Examiner, Art Unit 1625
/JOHN S KENYON/Primary Patent Examiner, Art Unit 1625
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