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 1-5 and 7-21, submitted on 9 August 2023, 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 10 February 2021.
Information Disclosure Statement
Two Information Disclosure Statements (IDSs), submitted on 9 August 2023 and 27 August 2024, 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 1 is objected to because of the following informalities: The structure of Compound I is of poor quality and is difficult to interpret. Appropriate correction is required.
Claim 4 is objected to because of the following informalities: Claim 4 claims a method for preparing the crystal forms of Claim 2. The Examiner believes “crystal forms” should be singular (“crystal form”). Appropriate correction is required.
Claim 18 is objected to because of the following informalities: There is a superfluous “and” in the limitation “malignant glioblastoma, and prostate adenocarcinoma, and advanced solid tumor” (Emphasis added). 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 7, 8, 10, 17, 18, 19, and 21 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 conditions which are mediated by cyclin dependent kinases, or the suppression of the proliferation of tumor cells which overexpress CDKs, does not reasonably provide enablement for the treatment of all cancers, nor does it enable the prevention of these conditions, such as 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 or preventing a disease associated with abnormal cell cycle regulation and suppressing the proliferation of at least one tumor cell comprising administering to a patient in need a therapeutically effective amount of the salt of Compound I of Claim 1. Compound I is an inhibitor of CDK4 and CDK6. Thus, the claims are directed to methods which can treat or prevent any form of cancer, or suppress the proliferation of any tumor cell, by administering a salt of Compound I to inhibit CDK4 and CDK6.
The state of the prior art and the predictability or unpredictability of the art:
Fassl (Science, 2022 January 14; 375(6577)) provides a review of CDK4 and CDK6 in cancer. CDK4 and 6 link the extracellular environment with the core cell-cycle machinery. Constitutive activation of CDK4/6 represents the driving force of tumorigenesis in several cancer types. Small molecule inhibitors of CDK4/6 have been used in the treatment of hormone receptor-positive breast cancers, and are in clinical trials for many other tumor types (Abstract). Currently approved therapeutics palbociclib, ribociclib, and abemaciclib are being tested in over 300 active or recruiting clinical trials for over 50 tumor types, such as other sub-types of breast cancers (HER2-positive, triple negative), as well as colon, lung, liver, uterine, and ovarian cancers, glioblastoma, and various lymphoid malignancies. The major impediment in the therapeutic use of these inhibitors is that patients who initially respond to treatment often develop resistance and eventually succumb to the disease. A substantial fraction of tumors show pre-existing, intrinsic resistance to CDK4/6-inhibitors (Outlook). CDK4 and CDK6 are expressed at constant levels throughout the cell-cycle (Page 3). Genomic aberrations of the cyclin D1 gene represent frequent events in different tumor types. Amplification of this gene is seen in many malignancies, for example in 13-20% of breast cancers, over 40% of head and neck squamous cell carcinomas, and over 30% of esophageal squamous cell carcinomas. A higher proportion of cancers, e.g., up to 50% of mammary carcinomas, overexpress cyclin D1 protein (Cyclin D-CDK4/6 in Cancer). Palbociclib, ribociclib, and abemaciclib were shown to block proliferation of several RB1-positive cancer cell lines, but not cell lines that have lost RB1-expression. Breat cancer cell lines representing the luminal, estrogen receptor-positive (ER+) subtype were shown to be most susceptible to arrest cell proliferation upon palbociclib-treatment (Validation of CDK4/6-inhibitors as anti-cancer agents). Only tumors with intact RB1 respond to CDK4/6-inhibitor treatment by undergoing cell-cycle arrest or senescence (Markers predicting response to CDK4/6-inhibition). The full-range of cyclin D-CDK4/6 function in tumor cells remains unknown. Hence, the impact of CDK4/6-inhibition on various aspects of tumorigenesis requires further studies (Outlook).
However, as described by Fassl, not all cancers can be successfully treated by inhibition of CDK4 or CDK6, and there is currently no known treatment that can be used to treat all forms of cancer. Additionally, there is no evidence in the prior art that cancers can be prevented.
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 of CDK4 or CDK6. Moreover, not all tumor cells have dysregulated CDK4 or CDK6 and would not be expected to be sensitive to inhibition of these two enzymes. Finally, there is no evidence in the current state of the art that a small molecule can be used to prevent the development of any form of cancer.
The amount of direction or guidance presented and the presence or absence of working examples:
Compound I is known in the art to be a CDK4 and/or CDK6 inhibitor, with the specification incorporating the prior art which demonstrates inhibition of these enzymes, as well as demonstrating that these compounds are effective in arresting the growth of several cancer cell lines in vitro. However, the specification, nor the art which is cited, demonstrates that this compound or its salts can prevent the development of conditions such as cancer, nor does the specification demonstrate the treatment of all forms of disease associated with abnormal cell cycle regulation, which includes cancer, nor does the specification demonstrate that this compound is capable of inhibiting the proliferation of all tumor cells. The specification provides data enabling the treatment of conditions which are mediated by CDK4 and/or CDK6, as well as the suppression of proliferation of tumor cells which have dysregulated CDK4 and/or CDK6.
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, 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)
Claims 5 and 13-16 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 5 is indefinite because the claim appears to be missing the phrase “compound” or “salt form” or similar in the limitation “comprising one or more selected from the salts of Compound I”.
Claims 13 and 15 are indefinite because the claims have limitations of “an XRPD pattern substantially as shown” and “DSC graph substantially as shown”. The specification does not define “substantially”, rendering the metes and bounds of the claims undefined, and therefore indefinite. It is not clear what would constitute a pattern or DSC graph which is “substantially as shown” in each referenced figure.
Claim 14 is indefinite because the claims have the limitation of “weak endothermic peaks”. What constitutes a weak endothermic peak versus a normal or strong endothermic peak is not defined in the specification, causing uncertainty as to whether an observed peak is weak or not, thus causing the metes and bounds to be undefined and therefore, indefinite.
Claims 13 and 14 are indefinite because there is no “or” or “and” prior to the final limitation of the Markush group.
Claim 16 is indefinite because the claim states that the ketone solvents include acetone, the ether solvents include tetrahydrofuran, the alcohol solvents include methanol, the ester solvents include ethyl acetate, the mixed solvent of a halogenated alkane and an alcohol solvent includes dichloromethane/methanol, the anti-solvent includes acetone and toluene, and the inert gas includes N2. It is unclear if the solvents and/or inert gas which is claimed is merely a part of the solvent system, or if these are meant to serve as representative solvents/gasses for use in the methods. The Examiner suggests changing the claim to read “the ketone solvent comprises acetone”, for example.
Claim 16 is indefinite because there is no “or” or “and” prior to the final limitation of the Markush group.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 2 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 2 depends on Claim 1, with Claim 1 claiming a single salt of Compound 1. Claim 2 claims the salt of compound I according to Claim 1, wherein the salt is one or more selected from the group consisting of several different polymorphic forms. Claim 2 is broader, and thus does not further limit Claim 1 as Claim 2 claims one or more salt forms of the compound of Claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 3 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 3 depends on Claim 1, with Claim 1 claiming a single salt of Compound 1. Claim 3 claims the salt of compound I according to Claim 1, wherein the salt of Compound I is a maleate, wherein the maleate of Compound I is one or more selected from the group consisting of three crystal forms, or wherein the salt of Compound I is a hydrochloride, wherein the hydrochloride is one or more selected from the group consisting of two crystal forms. Claim 3 is broader, and thus does not further limit Claim 1 as Claim 3 claims one or more salt forms of the compound of Claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claims 4 and 16 rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 4 and 16 are dependent on Claim 2, which is dependent on Claim 1, which claims a single salt form of Compound I. Claim 4 claims a method of producing the crystal forms of Compound I. Claims 4 and 11are broader, and thus does not further limit claim 1 as it is directed to multiple salt forms, while Claim 1 only claims a single salt form. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 11 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 11 is dependent on Claim 1, which claims a single salt form of Compound I. Claim 11 claims the salt of compound I wherein the salt is one or more selected from the group consisting of… Claim 11 is broader, and thus does not further limit claim 1 as it is directed to multiple salt forms, while Claim 1 only claims a single salt form. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 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, 5, 7-10, and 17-21 are rejected under 35 U.S.C. 103 as being unpatentable over Xia (US 2019/0010153; Publication Date: 10 January 2019) in view of Acharya (Dosage Form Design Considerations, Volume I, 2018, Pages 435-472).
Xia discloses nitrogen-containing fused heterocyclic compounds and their preparation. These compounds have a high inhibitor activity with respect to CDK4 and CDK9, and have significant inhibition of tumor cell proliferation associated with cyclin-dependent kinase activity (Abstract). One compound disclosed is compound I-52
PNG
media_image1.png
271
366
media_image1.png
Greyscale
(Page 21), which is identical to the compound claimed in the examined application. This compound has an IC50 against CDK4 of 3.88 nM, CDK6 of 3.81 nM, and CDK2 of 700 nM (Table 3, Page 141). Table 4 (Page 143) shows that this compound is active against MCF-7, T-47D, and ZR-75-1 cancer cells. The present invention also provides a composition, which comprises the nitrogen-containing fused heterocyclic compound, the pharmaceutically acceptable salt, the enantiomer, the diastereomer, the tautomer, the solvate, the metabolite or the drug precursor thereof, and at least a pharmaceutical excipient (Paragraph 0181). The term “pharmaceutically acceptable salt” refers to a salt formed by a suitable non-toxic organic acid, inorganic acid, organic base or inorganic base with compound I, which retains the biological activity of compound I. The organic acid can be various conventional organic acids in the art and capable of salt formation, preferably selected from the group consisting of methanesulfonic acid, p-toluenesulfonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, malic acid, lactic acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid, oxalic acid, succinic acid, benzoic acid, isethionic acid, naphthalenesulfonic acid and salicylic acid. The inorganic acid can be various conventional inorganic acid in the art and capable of salt formation, preferably selected from the group consisting of hydrochloric acid, sulfuric acid and phosphoric acid (Paragraph 0197). The present invention also provides a use of the nitrogen-containing fused heterocyclic compound, the pharmaceutically acceptable salt, the enantiomer, the diastereomer, the tautomer, the solvate, the metabolite or the drug precursor thereof in manufacturing medicament, the medicament is used for the prevention or the treatment of disorder associated with abnormal cell cycle regulation; the “disorder associated with abnormal cell cycle regulation” is preferably “disorder associated with abnormality of cyclin-dependent kinase (preferably CDK4 and/or CDK6)”, more preferably tumor, most preferably malignant tumor (e.g. breast cancer) (Paragraph 0178).
Xia does not explicitly disclose the salt forms claimed in Claim 1 of the examined application.
Acharya teaches the formation of salts in pharmaceutical development. Pharmaceutical salts are complexed with a counterion to produce a neutral complex compound, and the formation of pharmaceutical salts has become a popular approach in drug development because of the capability to produce an improved version of the drug. It is unrealistic to screen all possible counterions, but broad guidelines have been established to limit the selection process, such as the use of a negatively charged counterion for weakly basic drugs, the drug must be completely ionized and in a single state of ionization, and the pKa of the base and acid should differ minimally by a factor of 2. Around 50% of drug molecules approved by regulatory authorities and marketed as medicinal products are in salt forms. Thus, salt selection has become a common, standard operation during the drug development process (Abstract). Salt formation has several advantages, including enhancing the solubility and dissolution profile of the API, imparting enhanced chemical stability by inducing crystallinity, the crystalline form is practically easy to purify and more resistant to oxidation, the industrial processing of isolation and purification of drugs including the final step of their synthesis can be achieved using salt formation and is an economical alternative to chromatographic techniques, and salt formation can improve permeability across membranes leading to enhanced efficacy and efficiency of the drug (13.1.2 Merits and Demerits of Pharmaceutical Salts).
Xia and Acharya are considered analogous to the claimed invention as all are involved in the development of pharmaceuticals, and in particular, salt forms of pharmaceuticals. 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 generate the specific salt forms of the claimed compound, which is disclosed by Xia, in view of the teachings of Acharya that salt formation is a commonly done procedure in pharmaceutical development, allowing for improvements in the solubility, pharmacokinetics, and other physicochemical properties of the drug. The formation of salts of the compound of Xia is prima facie obvious use of a known technique to improve similar products in the same way (See MPEP § 2143 I (C)); Compound I-52 (Compound I of the examined application) is known in the art, while the formation of a salt is commonly employed in the pharmaceutical arts, predictably resulting in a form which has improved solubility. The artisan would be motivated to select this compound, and have a reasonable expectation of success, as Xia shows that this compound is a potent CDK4 and CDK6 inhibitor. Furthermore, the “mere selection of a particular salt from among a finite number of predictable options is generally considered obvious” (See MPEP § 2143 I (E)). One of ordinary skill in the art would have been able to narrow the group of potential salt-formers to a group of 53 anions known to form pharmaceutically acceptable salts, which would be an acceptable number to form a “reasonable expectation of success”.
Claims 1, 5, 7-10, and 17-21 are rejected under 35 U.S.C. 103 as being unpatentable over Shi (European Journal of Medicinal Chemistry, 178, 2019, 352-364) in view of Acharya (Dosage Form Design Considerations, Volume I, 2018, Pages 435-472).
Shi (See IDS, 9 August 2023) compounds which inhibit CDK4/6 (Abstract). One compound disclosed is compound 3d
PNG
media_image2.png
162
368
media_image2.png
Greyscale
which has variable R as
PNG
media_image3.png
49
69
media_image3.png
Greyscale
, and this compound inhibits CDK4 at 1.94 nM, CDK6 at 2.78 nM, and CDK2 at 145 nM, with activity against cancer lines (Table 1, Page 355).
Shi does not disclose pharmaceutically acceptable salts of this compound.
The teachings of Archarya are described previously and are fully incorporated into this rejection.
Shi and Acharya are considered analogous to the claimed invention as all are involved in the development of pharmaceuticals, and in particular, salt forms of pharmaceuticals. 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 generate the specific salt forms of the claimed compound, which is disclosed by Shi, in view of the teachings of Acharya that salt formation is a commonly done procedure in pharmaceutical development, allowing for improvements in the solubility, pharmacokinetics, and other physicochemical properties of the drug. The formation of salts of the compound of Shi is prima facie obvious use of a known technique to improve similar products in the same way (See MPEP § 2143 I (C)); Compound I-52 (Compound I of the examined application) is known in the art, while the formation of a salt is commonly employed in the pharmaceutical arts, predictably resulting in a form which has improved solubility. The artisan would be motivated to select this compound, and have a reasonable expectation of success, as Shi shows that this compound is a potent CDK4 and CDK6 inhibitor, and inhibits the proliferation of tumor cells. Furthermore, the “mere selection of a particular salt from among a finite number of predictable options is generally considered obvious” (See MPEP § 2143 I (E)). One of ordinary skill in the art would have been able to narrow the group of potential salt-formers to a group of 53 anions known to form pharmaceutically acceptable salts, which would be an acceptable number to form a “reasonable expectation of success”.
Regarding Claim 5, the formation of a pharmaceutical composition of this compound is prima facie obvious as the artisan would recognize that forming a composition would improve the delivery of this compound to the patient in need of treatment, and this technique is commonly employed in the pharmaceutical arts.
Regarding the methods claims, Shi demonstrates that this compound is a potent inhibitor of CDK4 and CDK6, and is effective at treating different tumor cell lines in vitro. Thus, it would be obvious to one of ordinary skill in the art to apply this known inhibitor of CDK4/6 to treat conditions which display abnormal cell cycle regulation, including cancer.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 5, 7-10, and 17-21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No. 10,662,186 (Patent Date: 26 May 2020) (‘186) in view of Acharya (Dosage Form Design Considerations, Volume I, 2018, Pages 435-472).
Claim 1 of ‘186 (See IDS, 9 August 2023) is directed to a compound which includes
PNG
media_image4.png
186
242
media_image4.png
Greyscale
, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, which is identical to the compound claimed in the examined application. Claim 2 of ‘186 is directed to a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. Claim 3 of ‘186 is directed to a method for inhibiting cyclin-dependent kinase activity in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. Claim 4 of ‘186 is directed to a method for inhibiting tumor cells in a subject comprising administering to the subject a therapeutically effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
‘186 does not specifically teach the claimed pharmaceutically acceptable salts.
The teachings of Archarya are described previously and are fully incorporated into this rejection.
‘186 and Acharya are considered analogous to the claimed invention as all are involved in the development of pharmaceuticals, and in particular, salt forms of pharmaceuticals. 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 generate the specific salt forms of the claimed compound, which is disclosed in ‘186, in view of the teachings of Acharya that salt formation is a commonly done procedure in pharmaceutical development, allowing for improvements in the solubility, pharmacokinetics, and other physicochemical properties of the drug. The formation of salts of the compound of ‘186 is prima facie obvious use of a known technique to improve similar products in the same way (See MPEP § 2143 I (C)); Compound I-52 (Compound I of the examined application) is known in the art, while the formation of a salt is commonly employed in the pharmaceutical arts, predictably resulting in a form which has improved solubility. The artisan would be motivated to select this compound, and have a reasonable expectation of success, as ‘186 shows that this compound is a potent CDK4 and CDK6 inhibitor, and inhibits the proliferation of tumor cells. Furthermore, the “mere selection of a particular salt from among a finite number of predictable options is generally considered obvious” (See MPEP § 2143 I (E)). One of ordinary skill in the art would have been able to narrow the group of potential salt-formers to a group of 53 anions known to form pharmaceutically acceptable salts, which would be an acceptable number to form a “reasonable expectation of success”.
Regarding the methods claims, this compound is a potent inhibitor of CDK4 and CDK6, and is effective at treating different tumor cell lines in vitro. Thus, it would be obvious to one of ordinary skill in the art to apply this known inhibitor of CDK4/6 to treat conditions which display abnormal cell cycle regulation, including cancer.
Conclusion
Claims 1-5 and 7-21 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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
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.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/P.M.R./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625