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 .
Status of claims
Pending claims 1, 9-10, 12, 15-17, 21-23, 40 and 42 have been examined on the merits.
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.
Claims 1, 9-10, 12, 15-17, 21-23, 40 and 42 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 recites administering “a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel,” thereby encompassing a broad functional genus of compounds. However, the specification identifies only three compounds, namely cilnidipine, Z160, and CNV2197944, no common structural features, as examples of compounds falling within the claimed genus. The specification does not describe any additional representative species, common structural features, a pharmacophore, or any structure-function correlation that would help a person of ordinary skill in the art (POSITA) to recognize which compounds belong to the claimed genus. The unpredictability of the claimed genus is illustrated by Seko (page 1901-1904) describing the synthesis and the structure-activity relationship (SAR) of numerous compounds based on an L- amino acid scaffold, all designed to achieve the same function objective of inhibiting both N-type and L-type calcium channels while maximizing selectivity for
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N-type channels to reduce cardiovascular side-effects associated with L-type blockade. Furthermore, Seko (page 1901-1904) further teaches that numerous structurally distinct compounds may be designed to achieve varying degrees of N-type selectivity, underscoring the scope and structural diversity of compounds potentially encompassed by the claimed functional genus. Therefore, the specification’s disclosure of only three exemplary compounds, without identification of structural characteristic common to the entire genus or a demonstrated structure-function relationship applicable across the claimed scope, does not reasonably convey possession of the entire genus of “a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel”. Therefore, the specification clearly fails to provide appropriate representative number of species commensurate with the scope of the claimed genus, and thus indicates that Applicant does demonstrate possession of the full scope of the claimed invention. (Seko, Takuya, et al. “Structure–Activity Study of l-Amino Acid-Based N-Type Calcium Channel Blockers.” Bioorganic & Medicinal Chemistry, vol. 11, no. 8, Apr. 2003, pp. 1901–13.)
Claims 1, 9-10, 12, 15-17, 21-23, 40 and 42, are directed to a method of treating complex regional pain syndrome (CRPS) by administering a dual N-type and L-type calcium channel blocker including cilnidipine. The claimed invention further encompasses biomarkers, dosing regimen, routes of administration, treatment intervals, and combination therapies. However, the specification does not provide any working example, experimental data, or other representative evidence demonstrating treatment of a subject having CRPS Type I or Type II with the claimed a dual N-type and L-type calcium channel blockers. The specification includes no example of oral administration, no example employing the claimed dosing intervals, and no examples of administrating an additional therapeutic agent to a subject in need thereof. Furthermore, although the claims encompass determining that a subject has abnormally elevated concentration of biomarkers, the specification does not describe any representative assay, protocol, or experimental results demonstrating assessment of these biomarkers before treatment or correlating such measurements with administration of the claimed compound. Additionally, the specification does not describe any treatment protocol, efficacy study, or expected outcomes such as reduction in pain intensity, improved physical function, and better coping mechanisms following administration of the claimed compounds. Instead, the disclosure relies primarily on mechanistic explanations, prophetic embodiments regarding the pharmacological properties of cilnidipine, Z-160, CNV2197944, or pharmaceutically acceptable salts as a method of treatment of various diseases including CRPS. Therefore, the specification does not reasonably convey to a POSITA the scope of the claimed methods at the time of filing.
The specification’s failures to disclose details on any specific regarding the claimed genus and method of treatment, further supports the conclusion that the specification lacks adequate written description of the claimed subject matter.
Claim Rejections - 35 USC § 103
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.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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, 9-10, 12, 15-17, 21-23, 40 and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Yamamoto et al., Eur. J. of Pharm., vol. 793, Dec. 2016, pp. 66–75 in view of Naleschinski et al., Curr Pain Headache Rep 14, 196–202 (2010), Koganei et al., Biol and Pharm Bulletin, vol. 32, no. 10, 2009, pp. 1695–700, Michael Gibson, https://www.wikidoc.org/index.php/Cilnidipine “Gibson”.
Regarding claims 1, 9-10, 12, and 15-16, Yamamoto (abstract) teach administering cilnidipine, a dual N-type and L-type voltage-gated Ca2+ channel blocker, to treat neuropathic pain. For example, Yamamoto (page 66-67) discloses cilnidipine attenuates mechanical allodynia and hyperalgesia, hallmarks of neuropathic pain, indicating that the dual N-type/L-type calcium channel blockade effectively alleviates neuropathic pain by suppressing central sensitization.
Yamamoto, however, does not explicitly mention complex regional pain syndrome (CRPS).
Naleschinski (page 196-197) discloses that CRPS Type I and Type II are neuropathic pain disorders, comprising two clinical pain syndromes: type I (reflex sympathetic dystrophy) and type II (causalgia). Therefore, it would have been obvious to a person of ordinary skill in the art (POSITA) to administer cilnidipine to a subject suffering from CRPS type I and Type II with a reasonable expectation of alleviating the neuropathic pain due to nerve injury.
Regarding claims 17 and 21-23, the combined teachings of Yamamoto and Naleschinski does not explicitly teach oral administration of cilnidipine at about 5 mg to about 25 mg.
Koganei (abstract) teaches oral administration of cilnidipine for pain relief. Koganei (page 1695-1697) teaches administration of oral cilnidipine to male Sprague-Dawley rats, weighing at doses of 3, 10 and 30 mg/kg 300—380g. This corresponds to about 9.0 mg to 11.4 mg of cilnidipine, which falls within the claimed dosage range as indicated in the instant claim. This is supported by Gibson discloses “In 24-hour clinical assessment, once-daily administration of cilnidipine (5–20 mg) ...” It is important to keep in mind that a once-daily dosing regimen necessarily separates successive administrations by approximately 24 hrs., which respectively require administration intervals of at least about 8 hrs. and at least 24 hrs. Therefore, it would have been obvious to a POSITA at the time of filing the invention to modify Yamamoto’s teachings in view of Yamamoto, Koganei and Gibson to administer oral cilnidipine to treat neuropathic pain because the combined references disclose dose ranges are effective for relieving pain, and to arrive at the claimed invention.
Regarding claim 40, Yamamoto does not explicitly mention elevated concentration of biomarkers.
However, Naleschinski (page 200) teaches that patients with CRPS exhibit elevated concentrations of inflammatory mediators, including TNF-α, IL-1β, and IL-6, and report increased levels of these cytokines are found in affected tissues and cerebrospinal fluid of CRPS patients. Accordingly, it would have been obvious to a POSITA to determine whether CRPS’ patients have elevated concentrations such as, TNF-α, IL-1β, and/or IL-6 prior to administering cilnidipine, as such biomarkers were recognized as characteristic of CRPS and their assessment constituted a routine diagnostic evaluation before treatment.
Regarding claim 42, the combined teachings of Yamamoto and Naleschinski does not explicitly teach administering an additional therapeutic agent to the subject.
Chaparro (page 1-2, 6, 9-12), however, discloses that monotherapy for neuropathic pain frequently provides inadequate analgesia and that combination pharmacotherapy, including add-on therapy with an additional therapeutic agent, is a recognized treatment strategy to improve analgesic efficacy. Chaparro (page 1-2, 6, 9-12), further teaches that a common clinical approach is to initiate treatment with monotherapy and pursue add-on combination therapy when the therapeutic response is incomplete. Therefore, it would have been obvious to a POSITA to further administer an additional therapeutic agent together with cilnidipine in the treatment of neuropathic pain in order to improve pain control, as taught by the recognized practice of combination pharmacotherapy.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PIERRE PAUL ELENISTE whose telephone number is (571)270-0589. The examiner can normally be reached Monday - Friday 8:00 am - 5:00 pm (EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JAMES H ALSTRUM-ACEVEDO can be reached at (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/P.P.E./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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