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 1-17, submitted on 12 November 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 15 June 2021.
Information Disclosure Statement
Two Information Disclosure Statements (IDSs), submitted on 13 December 2023 and 10 December 2025, are acknowledged and have been considered.
Claim Objections
Claim 1 is objected to because of the following informalities: Claim 1 claims “a heteroaryl group”. It should read “an heteroaryl group”. 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.
Claim 14 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 the treatment of neurodegenerative diseases which have upregulated or overexpressed LRRK2, it does not reasonably provide enablement for all neurodegenerative diseases. 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 a neurodegenerative disease, comprising administering to a patient in need a therapeutically effective amount of a compound of Claim 1. The specification shows that these compounds are inhibitors of both wild type and mutant LRRK2 (Table IV, Page 331). Thus, the claims are directed to a method which can be used to treat any neurodegenerative disease by inhibition of mutant or wild type LRRK2.
The state of the prior art and the predictability or unpredictability of the art:
Bova (International Journal of Molecular Sciences, 2024, 25, 11661) provides an overview of LRRK2 and its role in neurodegenerative diseases. An emerging role in neurodegenerative diseases is played by genetic mutations in the leucine-rich repeat kinase 2 (LRRK2) gene that cause increased LRRK2 activity with consequent alterations of neuronal autophagy pathways. LRRK2 kinase activity requires GTPase activity which functions independently of kinase activity and is required for neurotoxicity and to potentiate neuronal cell death. Important in the neurodegeneration process is the upregulation of casein kinase, which causes the alteration of the AMPK pathway by enhancing the phosphorylation of α-synuclein and huntingtin proteins, known to be involved in Parkinson’s and Huntington’s disease, and increasing the accumulation of amyloid-β protein for AD (Abstract). Other neurodegenerative conditions which are known to have involvement from dysregulated LRRK2 include ALS (Roles of LRRK2 on Other Neurodegenerative Diseases). However, not all neurodegenerative diseases can be treated in this manner as not all neurodegenerative diseases display overexpressed or upregulated LRRK2. For example, Creutzfeldt-Jakob disease is a neurodegenerative disorder which is caused by prions, leading to rapid cognitive decline, with no known involvement of LRRK2 in its pathogenesis. Thus, not all neurodegenerative diseases are known to have an involvement of LRRK2.
The relative skill of those in the art:
The artisan would generally have a medical degree and further training in neurology or neurodegenerative disease; 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 neurodegenerative diseases, as not all neurodegenerative diseases have upregulated or overexpressed LRRK2 driving their pathology.
The amount of direction or guidance presented and the presence or absence of working examples:
Table IV (Page 331) of the specification provides biological data for the compounds of the invention, showing that they are potent inhibitors of LRRK2. Thus, the specification enables the treatment of neurodegenerative conditions which have dysregulated LRRK2. The specification does not provide any biological data demonstrating the treatment of each and every neurodegenerative condition, such as those mediated by prions.
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 all neurodegenerative diseases due to the lack of evidence that all neurodegenerative diseases have dysregulated LRRK2 involved in their pathology, 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 § 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 and 13-17 are rejected under 35 U.S.C. 103 as being unpatentable over Cheng (US 2018/0127419; Publication Date: 10 May 2018) in view of Thornber (Chemical Society Reviews, Issue 4, 1979) and Sanphui (PLOS One, November 2013, 8, 11).
Cheng discloses a preparation method for a kinase inhibitor and a use thereof. The kinase inhibitor is represented by Formula (I)
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.The compound has a kinase inhibitory activity and therefore can be used for the preparation of medicines for treating kinase-activity related diseases (Abstract). The compounds of the invention are CDK kinase inhibitors (Paragraph 0009). Variable R1 and R2 can be connected with the adjacent N atom to form a ring structure, said ring structure includes a substituted or unsubstituted 3-12 membered saturated or unsaturated heterocycle or a bridged ring or spiro ring; wherein said heterocycle refers to a ring structure containing 0-3 heteroatoms selected from the group consisting of N, O, or S, in addition to the nitrogen atom attached to the parent nucleus (Paragraph 0012). One compound of the invention is
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. This compound has variable R1 as heteroaryl substituted with heterocycloalkyl and variable R2 as heterocycloalkyl that is attached via a nitrogen atom. An embodiment
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(Page 3) contains an oxygen-containing heterocycle in the variable R2 position. Five-membered rings in the variable R2 position are also envisioned in the disclosed compounds
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(Page 6). In the third aspect of the present invention, the use of the compound of formula I described in the first aspect of the present invention is provided, the compound of formula I is used for preparation of a medicament for the treatment of a disease associated with CDK kinase activity (Paragraph 0052-0053). The pharmaceutical composition of the invention comprises the compound of the invention in a safe and effective dose and a pharmaceutically acceptable carrier (Paragraph 0085). The compounds are also used in the treatment of disease associated with CDK kinase activity or expression quantity (Paragraph 0147). The CDK kinase is selected from the group consisting of CDK4, CDK6, or a combination thereof (Paragraph 0148).
Cheng does not disclose a compound wherein the heterocycle is attached via the carbon in the variable R2 position, nor does Cheng explicitly disclose the treatment of neurodegenerative diseases using their compounds.
Thornber teaches the concept of bioisosterism, which is the concept wherein groups or molecules which have chemical and physical similarities produce broadly similar biological properties (Page 563). Table 1 (Page 564) lists the classical isosteres, and includes ring equivalents. Such ring equivalents include -CH2-, -N-, and -O-. These atoms have similar electronic properties and as such, their replacement within a ring system is not expected to significantly alter the properties of that ring.
Sanphui teaches the role of CDK4 in neurodegenerative disease, specifically in Alzheimer’s disease. Aberrant activation of cell cycle regulatory proteins is implicated in neurodegenerative disease including AD. The authors tested the efficacy of Cdk4 specific inhibitors as neuroprotective agents in cellular models of neuronal cell death. The authors found that several inhibitors protected neuronal cells against death induced by nerve growth factor deprivation and oligomeric beta amyloid that are implicated in AD. These neuroprotective agents inhibit specifically Cdk4 kinase activity, loss of mitochondrial integrity, induction of pro-apoptotic protein Bim and caspase 3 activation in response to NGF activation. The authors propose that Cdk4 inhibition would be a therapeutic choice for ameliorating neurodegeneration and could lead to the development of effective drugs for AD.
Cheng, Thornber, and Sanphui are considered analogous to the claimed invention as all are involved in the development of pharmaceuticals for the treatment of disease. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to modify the CDK4 inhibitors of Cheng by altering the position of the binding of the heterocycle in the variable R2 position, and further modifying this ring to replace the nitrogen with oxygen, and apply these compounds for the treatment of neurodegenerative diseases as taught by both Thornber and Sanphui. The artisan would not expect altering the binding site of the heterocycloalkyl ring to significantly alter the properties of the resulting compound due to the close chemical structure (See MPEP § 2144.09 I). The artisan would also not expect replacing the ring nitrogen with -O- to significantly alter the properties of the resulting compound as Thornber teaches that -NH-, -O-, and -CH2- function as ring equivalents, and thus the artisan would not expect the properties of these compounds to be significantly altered by performing this substitution as due to the close chemical structure (See MPEP § 2144.09 I). Regarding the use of a five-membered oxygen containing heterocycle, Cheng discloses embodiments with both 5- and 6-membered rings, and as such, the artisan would not expect replacing a six-membered ring system with a five membered ring to result in a compound with significantly different properties due to the close chemical structure (See MPEP § 2144.09 I). As Sanphui has established the link between CDK4 and neurological diseases such as AD and Parkinson’s Disease, it would be obvious to one of ordinary skill in the art to apply these CDK4 inhibitors for the treatment of these conditions. Amyloid beta is a known protein which is associated with cognitive decline in both Parkinson’s disease and Alzheimer’s disease.
Claims 1-5 and 13-17 are rejected under 35 U.S.C. 103 as being unpatentable over Brain (WO 2007/140222; Publication Date: 6 December 2007) in view of Sanphui (PLOS One, November 2013, 8, 11).
Brain discloses organic compounds that are useful for the treatment, prevention, and/or amelioration of diseases, particularly pyrrolopyrimidine compounds and derivatives are described which inhibit protein kinases (Abstract). In one embodiment, the protein kinase-associated disorder is selected from the group which includes nervous system diseases (Page 4, Lines 24-27). These compounds are modulators of JAK1, JAK2, JAK3, as well as CDK1 through CDK9 (Page 7, Lines 4-6). Compounds are of the formula I
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. R2 and R3 are selected from the group consisting of hydrogen, hydroxyl, alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl, each of which may be optionally substituted. R4 is selected from hydrogen, alkyl, substituted alkyl, substituted or unsubstituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. When the bond between X and Y is a double bond, X is N or CR11, and Y is CR12 (Page 7, Lines 14-30). Variable R12 is selected from the group consisting of halo, hydrogen, alkyl, alkoxy, CN, and optionally substituted ring systems (Page 8, Lines 3-11). One compound disclosed is Compound 228
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(Page 125). Another is Compound 235
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(Page 127). These compounds have variable R1 as phenyl substituted with heterocycle, which is either unsubstituted or substituted with and alkyl carbonyl group and variable R2 as heterocycloalkyl attached via the carbon atom. However, these compounds do not have a nitrile (-CN) moiety. Compounds 393, 394 (Page 169) 395, and 396 (Page 170) provide embodiments which contain a cyano group at variable R12
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. Table E (Page 193) has the biological activity data for the compounds of the invention. Compounds 394, 395, and 396 each have IC50 of less than 1 µM against CDK4, indicating that the cyano group is conducive to a potent inhibitor of CDK4. Compound 228 has an IC50 of less than 10 µM against CDK4 and CDK2cyA. The invention provides a pharmaceutical composition of any compounds of the present invention and a pharmaceutically acceptable carrier or excipient (Page 49, Lines 9-11). The compounds of the invention are suitable as active agents in pharmaceutical compositions that are efficacious particularly for treating protein kinase-associated disorders (Page 49, Lines 17-19).
Brain does not explicitly disclose the treatment of neurodegenerative diseases such as Alzheimer’s disease or Parkinson’s disease.
The teachings of Sanphui are previously described and fully incorporated into this rejection.
Brain and Sanphui are considered analogous to the claimed invention as all are involved in the use of protein kinase inhibitors for the treatment of diseases. 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 apply compound 228 or 235 of Brain modified to include a cyano group in the same position as the compounds of the examined application for the treatment of neurodegenerative diseases such as AD or Parkinson’s disease as Sanphui demonstrates that CDK4 inhibition prevents neuronal cell death when cells are treated with pathogenic stimulants associated with both conditions. As Sanphui has established the link between CDK4 and neurological diseases such as AD and Parkinson’s Disease, it would be obvious to one of ordinary skill in the art to apply these CDK4 inhibitors for the treatment of these conditions. Amyloid beta is a known protein which is associated with cognitive decline in both Parkinson’s disease and Alzheimer’s disease.
Regarding the addition of the nitrile (-CN) moiety, this modification is disclosed as a modification at the same position as the compounds of the examined application. Further, Brain provides embodiments demonstrating that compounds which have this moiety are potent inhibitors of CDK4, providing both a motivation and reasonable expectation of success for modifying compounds 228 or 235. Regarding the use of a five-membered oxygen containing heterocycle, compounds 228 and 235 both contain a six-membered oxygen containing heterocycle, and the artisan would not expect modifying these compounds to have a five-membered ring to have significantly different properties due to the close chemical structure (See MPEP § 2144.09 I).
Allowable Subject Matter
Claim 11 is allowed.
Claims 6-10 and 12 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is an examiner’s statement of reasons for allowance: There is no prior art which teaches or suggests the compounds as claimed in examined Claim 11 (See STN Search, Search Notes). The compounds of Claim 11 require a substituted pyrazolyl group with substituents distinct from those disclosed by Cheng and Brain, and an optionally substituted tetrahydrofuran, optionally substituted oxetanyl, optionally substituted tetrahydropyran, or optionally substituted alkoxylalkyl moiety. The closest prior art comes from Cheng (US 2018/0127419; Publication Date: 10 May 2018) and Brain (WO 2007/140222; Publication Date: 6 December 2007), cited above. Cheng and Brain disclose compounds with phenyl or 6-membered heteroaryl rings in the analogous variable R1 position, as well as heterocycles in the analogous R2 position. However, there is no teaching, suggestion, or motivation within these references to replace the six-membered rings in the R1 position with the five-membered heteroaryl ring claimed in examined Claims 6-10, nor is there any teaching, suggestion or motivation to replace the heterocycles which are claimed with alkoxyalkyl groups as claimed in the examined application. Both Brain and Cheng disclose distinct methods of synthesizing their compounds that do not teach, suggest, or provide motivation for modification to arrive at the claimed method. The compounds of Brain use intermediates such as
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(Page 103) in their synthesis, and does not disclose the use of intermediates analogous to Compounds 11X or 15X of the examined application. Cheng a preferred reaction method in paragraph 0038. The method disclosed in Paragraph 0038 is as follows:
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. Compound I-6 is analogous to Compound 11X, replacing the methyl sulfonyl leaving group with chlorine. However, Compound I-7 is distinct from Compound 15X, lacking the carbonyl moiety as claimed in the examined method.
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee. Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”
Conclusion
Claims 1-5 and 13-17 are rejected.
Claims 6-10 and 12 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim 11 is allowed.
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 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
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