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 .
Current Status of 18/569,519
This Office action is responsive to the claims of 10/10/2024, claims 54-83 are pending in the application and have been examined on the merits.
Priority
The instant application is a national stage entry of PCT/EP2022/066504, filed 06/16/2022, which claims priority to GB patent application No. 2108572.5, filed 06/16/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/22/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
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.
Claim 82 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating proliferative disorder, cancer, myotonic dystrophy, ALS, spinal muscular atrophy, and Fragile X syndrome, comprising administering a compound according to claim 54, does not reasonably provide enablement for treating other diseases/disorders comprising administering a compound according to claim 54. 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.
To be enabling, the specification of the patent application must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). Explaining what is meant by “undue experimentation,” the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
The factors to be considered in determining whether a disclosure meets the enablement requirements of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir., 1988). The court in Wands states, “Enablement is not precluded by the necessity for some experimentation, such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue’, not ‘experimentation’” (Wands, 8 USPQ2sd 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations” (Wands, 8 USPQ2d 1404). Among these factors are: (1) the nature of the invention; (2) the breadth of the claims; (3) the state of the prior art; (4) the predictability or unpredictability of the art; (5) the relative skill of those in the art; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
(1) The nature of the invention and (2) the breadth of the claims:
The claims are drawn to methods of treating disorders in a subject comprising administering to the subject a compound according to claim 54. The genus of compounds recited in claim 54 is immense, having numerous variably defined substituents therein. Claim 82 recites a method of treating a disorder in a subject comprising administering to the subject a therapeutically effective amount of the compound of claim 54. Claim 82 specifies that the disorders amenable to the treatment method include proliferative disorder; cancer; a viral infection; HIV; a neurodegenerative disorder; Alzheimer’s disease; Parkinson’s disease; ischaemia; a renal disease; a cardiovascular disorder; atherosclerosis; and autoimmune disorder; rheumatoid arthritis; systemic lupus erythematosus; psoriasis; Sjogren’s syndrome; a disorder caused by dysfunction of translation in cells; muscular dystrophy; myotonic dystrophy; amyotrophic lateral sclerosis; spinal muscular atrophy; or Fragile X syndrome. These claims encompass the treatment of everything from cancer to HIV infection (viral infection) to Alzheimer’s disease (neurodegenerative disease) to multiple sclerosis (autoimmune disease) to diabetic nephropathy (renal disease). Thus, the claims taken together with the specification imply that all compound of claim 54 are capable of treating all forms of disease recited in claim 82. The breadth of the claims is extremely broad. The nature of the invention and the breadth of the claims weighs against enablement for the full scope of the claimed invention.
(3) The state of the prior art and (4) the predictability or unpredictability of the art:
It is well established in the literature that there is a plethora of disorders that might affect a subject and each disorder is a reflection of different causative factors and different cellular behaviors. One compound capable of treating one type of disorder in unlikely to be useful in treating other types of disorders. For example, those skilled in the art would not use a chemotherapeutic agent effective in the treatment of cancer to treat a neurodegenerative disease such as Alzheimer’s disease. Likewise, antiviral agents effective at treating viral infections would not be used to also treat cardiovascular disease.
Applicants have proffered no nexus or link between CDK and the disorders encompassed by the instant claims, other than cancer which is well established in the art to be amenable to treatment with CDK inhibitors. Liu (Lui, Goldie Y L et al. “CDK12: an emerging therapeutic target for cancer.” Journal of clinical pathology vol. 71,11 (2018): 957-962. doi:10.1136/jclinpath-2018-205356) teaches that CDK12 is an emerging therapeutic target for cancer. Hayes et al. (US 2019/0038625 A1) have shown that CDK 12 inhibition is capable of treating myotonic dystrophy, ALS, spinal muscular atrophy, and Fragile X syndrome. The scope of enabled diseases to be treated through inhibition of CDK12 is further discussed in Tang et al. (Tang, Ruijun, et al. "A patent and literature review of CDK12 inhibitors." Expert Opinion on Therapeutic Patents 32.10 (2022): 1055-1065.) The involvement of CDK12 in other diseases/disorders is not well-known or established in the art.
The treatment of proliferative disorders; cancers; viral infections; neurodegenerative disorders; ischaemia; renal diseases; cardiovascular disorders; autoimmune disorders; or disorders caused by dysfunction of translation in cells with the same compounds is not considered enabled. No compound (let alone a genus of compounds as broad as that presently claimed) has ever been found that can treat proliferative disorders; cancers; viral infections; neurodegenerative disorders; ischaemia; renal diseases; cardiovascular disorders; autoimmune disorders; or disorders caused by dysfunction of translation in cells generally, even though massive efforts have been directed towards this end. Such a genus of compounds would be considered by those skilled in the art a “magic bullet” effective to treat virtually every disorder known to man. Since this assertion is contrary to what is known in medicine, proof must be provided that this revolutionary assertion has merits. Nearly all drugs are effective against only a limited group of related diseases/disorders. Therefore, a compound effective against proliferative disorders; cancers; viral infections; neurodegenerative disorders; ischaemia; renal diseases; cardiovascular disorders; autoimmune disorders; or disorders caused by dysfunction of translation in cells generally would be a revolutionary exception. Applicant is asserting that they succeeded where others have failed. Where extensive efforts have all failed, it is reasonable for the Patent and Trademark Office to require proof that the claimed invention actually works for this specific utility. It is well established that a utility rejection is proper when scope of enablement is not reasonably correlated to the scope of the claims. (In re Vaeck 20 USPQ2d 1439, 1444, In re Ferens 163 USPQ 609).
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation’.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
It is well established that "the scope of enablement varies inversely with the degree of unpredictability of the factors involved” and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 166 USPQ 18, at 24 (In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved.), Nationwide Chemical Corporation, et al. v. Wright, et al., 192 USPQ 95 (one skilled in chemical and biological arts cannot always reasonably predict how different chemical compounds and elements might behave under varying circumstances), Ex parte Sudilovsky 21 USPQ 2d 1702 (Appellant's invention concerns pharmaceutical activity. Because there is no evidence of record of analogous activity for similar compounds, the art is relatively unpredictable) In re Wright 27 USPQ2d 1510 (the physiological activity of RNA viruses was sufficiently unpredictable that success in developing specific avian recombinant virus vaccine was uncertain). As long as the Specification discloses at least one method of making and using the claimed invention that bears a reasonable correlation to the entire scope of the claim, then the enablement requirement of 35 U.S.C. 112, 1st Paragraph is satisfied. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). To that extent, if little is known in the prior art about the nature of the invention and the art is unpredictable, the Specification would need more detail as to how to make and use the invention in order to be enabling. See Chiron Corp v. Genetech, lnc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004) ("Nascent technology, however, must be enabled with a specific and useful teaching. The law requires an enabling disclosure for nascent technology because a person of ordinary skill in the art has little or no knowledge independent from the patentee's instruction. Thus, the public's end of the bargain struck by the patent system is a full enabling disclosure of the claimed technology.")
(5) The relative skill of those in the art:
The artisan would have experience in medicinal chemistry, organic chemistry, pharmaceutical sciences, or a related field. The artisan would have experience in the synthesis and discovery of small-molecule pharmaceuticals, including the design and optimization of protein kinase inhibitors. The artisan would be familiar with kinase assay methodologies, structure activity relationships, and pharmacokinetic and development principles.
Despite a high skill in the art, the artisan would be unable to predict or identify inhibitors capable of treating the vast breadth of unrelated diseases encompassed by the claims. This uncertainty highlight the inherent unpredictability of translating CDK inhibition into therapeutic efficacy across diverse pathological contexts.
(6) The amount of direction or guidance presented and (7) the presence or absence of working examples:
The specification provides in vitro assays for determining whether a claimed compound is an inhibitor of CDK7 and/or CDK12 and provide cyclin K degrader activity. Applicants have screened a handful of the claimed compounds for their inhibition and degrader activity and presented the results in Tables 1 and 2 of the specification.
However, the specification does not provide any in vivo examples demonstrating successful treatment of any disorder in a subject with the compounds of the invention. Applicants do not disclose or describe any in vivo models of any disorder for testing their compounds for in vivo therapeutic activity.
The specification does not provide any direction or guidance for determining the particular administration regimens necessary to treat all the various types of disorders claim, particularly in humans. Applicants have merely listed disorders they purport can be treated with the claimed genus of compounds (pg. 91-100) without providing any information regarding the treatment regimens. Applicants disclose that the compounds can be administered by any route (pg. 101), formulated in any type of formulation (pg. 101-106), and administered in any dose in the range of about 10mg to about 250mg per kilogram of body weight of the subject (pg. 107). This is a 25,000-fold range of doses.
Applicants have provided no working examples correlating inhibition of CDK12 in vitro with efficacy in the treatment of any disorder using the claimed compounds.
(8) The quantity of experimentation necessary:
Considering the state of the art as discussed by the references above, particularly with regards to the lack of correlation between CDK12 inhibition and the treatment of all claimed disorders and the high unpredictability in 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 in the scope of the claims.
Genentech Inc. vs. Nova Nordisk states, "[A] patent is not a hunting license. It is not a reward for a search but a compensation for its successful conclusion and ‘patent protection’ is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable” (42 USPQ 2d 1001, Fed. Circuit 1997).
In the instant case, Applicants have presented a general idea that because 91 species of the instantly claimed genus of compounds inhibit CDK12 in vitro they must therefore, a priori, be useful in the treatment of any and all disorders that are “associated with” cyclin-dependent protein kinases (CDK); result from an “inappropriate activity” of a CDK; are “associated with” CDK mutation; are “associated with” CDK overexpression; are “associated with” upstream pathway activation of CDK; or are ameliorated by the inhibition of CDK. Such disorders are disclosed (and claimed) to include at least proliferative disorders; cancers; viral infections; neurodegenerative disorders; ischaemia; renal diseases; cardiovascular disorders; autoimmune disorders; or disorders caused by dysfunction of translation in cells.
However, the claims encompass a multitude of compounds (perhaps millions) having a plethora of chemically and biologically distinct substituents. Applicants synthesized and tested 100 compounds with very similar core structures (see Claim 77). It is evident that a very small percentage of the claimed genus of compounds were actually synthesized and tested (for CDK7 and CDK12 inhibition in vitro) by Applicants and all of the synthesized compounds were related in structure. Additionally, Applicants provide no reasonable nexus between inhibition of CDK12 and the treatment of any disease/disorder other than cancer. Neither does the prior art recognize such a nexus, i.e., there is no evidence in the art that inhibition of CDK12 would be therapeutically effective in the treatment of all viral infections; neurodegenerative disorders; ischaemia; renal diseases; cardiovascular disorders; autoimmune disorders; and disorders caused by dysfunction of translation in cells as presently claimed.
Determining if any particular claimed compound would treat any particular disease state would require synthesis of the compound, formulation into a suitable dosage form, and subjecting it to clinical trials or to testing in an assay known to correlate to clinical efficacy of such treatment. This is undue experimentation given the scope of the claims, the state and predictability of the art, and the limited guidance and direction provided by Applicants.
Accordingly, the instant claims do not comply with the enablement requirement of 35 U.S.C. § 112, first paragraph, since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
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.
Claims 54-68, and 73-83 are rejected under 35 U.S.C. 103 as being unpatentable over Bondke (WO 2015/124941, found in IDS filed 10/22/2024) in view of Slabicki (Słabicki, Mikołaj, et al. "The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K." Nature 585.7824 (2020): 293-297, found in IDS filed 10/22/2024) and Bauer (Bauer, Matthias R., et al. "Put a ring on it: application of small aliphatic rings in medicinal chemistry." RSC Medicinal Chemistry 12.4 (2021): 448-471.).
Bondke teaches pyrazolo[1,5-a]pyrimidine-5,7-diamine compounds and their use in the treatment of CDK mediated diseases. The reference teaches these compounds as compositions comprising the compound and a pharmaceutically acceptable carrier or diluent (claim 95); a method of preparing a composition comprising mixing the claimed compound and a pharmaceutically acceptable carrier or diluent (claim 96); a method of inhibiting CDK function in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of the claimed compound (claim 97); a method of regulating (e.g., inhibiting) cell proliferation (e.g., proliferation of a cell), inhibiting cell cycle progression, promoting apoptosis, or a combination of one or more these, in vitro or in vivo, comprising contacting a cell with an effective amount of the claimed compound (claim 98); and teaches methods of treating a disorder comprising administering the claimed compounds to a subject in need thereof (pg. 10, lines 34-38), the disorders are specified on pg. 58 lines 21-26 and includes proliferative disorders and cancers. The treatment further comprises treatment with additional active ingredients including a Her2 blocker and chemotherapeutic agents (Abstract).
One disclosed compound is PPDA-001
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(pg. 44), which has the following substitutions according to the formula of instant claim 54: L7 is -CH2-; Ar1 is phenyl; X5 is -NH-; L5 is -CH2-; Cy5 is Cy5A, Cy5A is a C5 heterocycle that contains one nitrogen ring atom (6-membered heterocycle), the Cy5A ring is substituted with an -RCy5AC group which is -OH, Cy5 is (3R, 4R)-3-hydroxy-piperidin-4-yl group; R3 is an iso-propyl group. PPDA-001 differs from the instantly claimed compounds at positions R3 and Ar2. However, these substitutions are obvious modifications of PPDA-001.
Slabicki teaches that CR8
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is a CDK inhibitor and that CR8 has a solvent-exposed pyridyl moiety that induces the formation of a complex between CDK12–cyclin K and the CUL4 adaptor protein DDB1, bypassing the requirement for a substrate receptor and presenting cyclin K for ubiquitination and degradation (Abstract). The reference goes on to empirically show that the phenylpyridine functionality that contains a 2-pyridyl group is essential for complex formation between DDB1 and CDK12 (Fig 3, pg. 296; CR8 phenylpyridine confers glue activity section pg. 296).
Bauer teaches that cyclopropane (CyPr) rings are the most ubiquitous small ring system in medicinal chemistry and is consistently the most frequently used small ring in patent literature due to its unique structure and physiochemical properties (pg. 449, right column second para.). The reference teaches that CyPr groups are extensively used in medicinal chemistry because they can increase potency, provide conformational stability, and improve pharmacokinetics and solubility of drug compounds (pg. 449, right column, second to last para.). CyPr groups are also frequently used as isosteres for small alkyl groups such as isopropyl. The reference then goes on to provide specific examples highlight the utility of the incorporation of CyPr groups into medicinal chemistry applications (see pg. 449-453).
The artisan would have experience in the design, synthesis, and evaluation of small-molecule CDK inhibitors for therapeutic use. The artisan would have experience in organic chemistry, medicinal chemistry, pharmaceutical sciences, or a related field. The artisan would be familiar with techniques used to optimize potency, selectivity, and drug-like properties of promising compounds. The artisan would also be familiar with previously reported CDK inhibitors. The artisan would understand common medicinal chemistry principles such as bioisosteric replacement, scaffold modification, and functional group optimization to improve pharmacokinetic and pharmacodynamic properties.
Bondke identifies PPDA-001 as a CDK12 inhibitor, the artisan would have been motivated to modify PPDA-001 to further optimize its activity and properties for the treatment of CDK12-associated disorders.
With respect to the substituents Ar1 and Ar2, Slabicki teaches that the 1,4-phenylene moiety at Ar1 connected to a pyridine-2-yl group at Ar2 is essential for the formation of the CDK12-DDB1 complex, which is implicated in ubiquitination and degradation pathways associated with CDK12 function. Based on this, the artisan would have been motivated to incorporate this moiety into their compound in order to more effectively modulate CDK12-mediated biological process. This represents a logical modification to the core molecule and constitutes routine optimization of a know CDK12 inhibitor.
Regarding the R3 group, Bauer teaches that CyPr groups are common isosteres of isopropyl groups in medicinal chemistry and are frequently employed to modulate physiochemical and ADME properties. Because PPDA-001 contains an isopropyl group, the artisan would have been motivated to substitute this group for a CyPr group as part of routine isosteric modification to improve or optimize the drug-like properties of the compound without significantly altering its CDK12 inhibitory activity.
Accordingly, the combination of references Slabicki and Bauer would have rendered the instantly claimed compounds obvious, as the proposed modifications represent predictable, routine changes made by the artisan to optimize a known CDK12 inhibitor for therapeutic use.
Conclusion
Claims 54-68, and 73-83 are rejected.
Claims 69-72 are objected to as being dependent upon a rejected base claim.
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/C.K.E./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625