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 .
DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06/11/2026 has been entered.
Status
Claims 14, 24, and 34-36 are pending and presented for examination.
Priority
This application is a 371 of PCT/EP2019/079170, filed 10/25/2019, which claims priority to foreign application SE1851333-3 filed 10/26/2018.
Information Disclosure Statement
No Information Disclosure Statements was filed with Applicant’s response.
Withdrawn Claim Rejections
Claim 34 was 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. Applicant’s amendment and corresponding reply pertaining to the newly added limitation have overcome the 35 U.S.C. 112(d) rejection made of record in the previous Office Action, specifically, the addition of the limitation to claim 34 that requires 5 mg to 30 mg mepivacaine.
Claim Rejections - 35 USC § 103
Rejection maintained
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 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 non-obviousness.
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 14, 24, and 34-36 are rejected under 35 U.S.C. 103 as being unpatentable over
Jahangiri (Orthop. Sci (2014) 19:737–743. DOI 10.1007/s00776-014-0587-2) in view of
Migliore et al. (cited by 4/26/2021 IDS), taken in further view of
Bernstein, Joseph (US 20090131442 A1 – cited by IDS),
Ambriz-Tututi et al. (European Journal of Pharmacology, Volume 512, Issues 2–3, 2005, Pages 121-127, ISSN 0014-2999, https://doi.org/10.1016/j.ejphar.2005.01.055), and
Cobalt et al. (Operative Techniques in Sports Medicine; Volume 25, Issue 1, March 2017, Pages 41-49.)
Claimed invention
The invention is drawn to treating osteoarthritis (OA) in a horse comprising administering:
0.01-0.10 mg sildenafil,
5-30 mg mepivacaine and
10-1000 mg glucose (a.k.a. “dextrose”)
by injection into an affected joint of the horse.
Prior art
Jahangiri teaches about a clinical trial that used local intraarticular injection of dextrose (DX) and the local anaesthetic, lidocaine, for the treatment of osteoarthritis. See title and abstract. Jahangiri specifically teaches injection of 0.5 ml of 20% (i.e., 100 mg) dextrose (DX) and 0.5 ml of 2% (i.e., 10 mg) lidocaine. See abstract; see also p. 740, 1st column. The injection was repeated monthly. See Id.
While Jahangiri teaches the treatment of osteoarthritis with intraarticular injection of 100 mg dextrose and 10 mg lidocaine, Jahangiri does not expressly teach administration of 1) mepivacaine and 2) sildenafil or 3) treatment of a horse.
Regarding 1) mepivacaine:
Mepivacaine, like lidocaine, is a local anaesthetic that is known to be beneficial for ameliorating OA. For example, Migliore teaches intra-articular (IA) mepivacaine administration provided improvement for treatment of OA. See title; abstract; p. 3, 2nd col. A person of ordinary skill in the art (POSA) would have found it obvious to combine mepivacaine with dextrose, i.e., glucose, and lidocaine for treating OA because Jahangiri discloses the combination of dextrose and lidocaine for treating OA in humans and Migliore teaches OA can also be treated with mepivacaine. The artisan would have sought to combine the ingredients together for the purpose of using them for what they were already known to be useful for, i.e., treating OA. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Alternatively, the POSA would have found it obvious to replace the OA-treating local analgesic, lidocaine, with another known OA-treating local analgesic such as mepivacaine. The POSA would have also found it obvious to use mepivacaine at similar amounts disclosed for lidocaine, i.e., 10 mg, since both are known local analgesics that have OA-treating effects. The POSA would have had a reasonable expectation of success that mepivacaine would provide OA-treating effects.
Regarding 2) sildenafil:
Bernstein teaches the use of a PDE5 inhibitor for treating OA. See title; abstract; see also Claims 1-3. The PDE5 inhibitor can be administered by multiple routes including intramuscular, intravenous, and oral routes and is selected from sildenafil, avanafil, tadalafil, udenafil, vardenafil and zaprinast. See Claims 5-10. It can be administered to humans or nonhuman mammals. See Claims 11-12. The inhibitor is administered at doses of 50 mg or less. See Claim 14. One of ordinary skill in the art would have found it obvious to combine PDE5 inhibitor (e.g., sildenafil, tadalafil, udenafil, or avanafil) with dextrose and a mepivacaine for treating OA in a humans or nonhuman mammal because the combination of Jahangiri and Migliore suggests treating OA with a combination of mepivacaine with dextrose while Bernstein teaches the a human or nonhuman mammal with OA can also be treated with a PDE5 inhibitor (e.g., sildenafil, tadalafil, udenafil, or avanafil). The POSA would have sought to combine a PDE5 inhibitor such as sildenafil together with dextrose and mepivacaine for the purpose of using them for what they were already known to be useful for, i.e., treating OA. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Regarding the claimed amount of 0.01-0.1 mg sildenafil, Bernstein teaches sildenafil is used at a dose amount of 50 mg or less (see 0020, 0027; Claims 7 and 14) and those of ordinary skill in the art will recognize that the exact dosage of the medication to be administered may vary depending on factors such as the age, gender, weight and health status of the individual patient, as well as on the precise nature of the condition being treated. See 0019. Ambriz-Tututi further teaches local peripheral administration of sildenafil at 50-200 μg, specifically disclosing 50 μg, 100 μg, and 200 μg, (0.05-0.2 mg) and that sildenafil produced dose-related antinociception, thereby demonstrating that the amount of locally administered sildenafil was a result-effective variable (Ambriz-Tututi, “3.1. Peripheral and spinal antinociceptive effects of sildenafil”; Fig. 1A-C.) Given that the amount of sildenafil to be administered and the precise treatment protocol should be determined by a skilled practitioner such as a physician and further given that the medication is administered in an amount sufficient to reduce pain associated with osteoarthritis, a POSA would have found it obvious to adjust the amount to effectively reduce pain and, therefore, optimize the treatment of OA. Accordingly, the POSA would have found the claimed amount of 0.01-0.1 mg (Claim 14 and Claim 34) sildenafil to be obvious. Additionally, Ambriz-Tututi’s disclosed range of 0.05-0.2 mg sildenafil overlaps the claimed dose range of 0.01-0.1 mg (Claim 14 and Claim 34), including Ambriz-Tututi’s expressly disclosed doses within the claimed range, the claimed range is rendered obvious. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. MPEP 2144.05 [R5]. Note, while the prior art does not disclose the exact claimed values, but does overlap, in such instances even a slight overlap in range establishes a prima facie case of obviousness. In re Peterson, 65 USPQ2d 1379, 1382 (Fed. Cir. 2003). Here, Ambriz-Tututi’s disclosed range of 0.05-0.2 mg sildenafil overlaps and therefore renders obvious the claimed dose range of 0.01-0.1 mg.
Regarding 3) treatment of a horse:
As outlined above, the combined teachings of Jahangiri, Migliore, Bernstein and Ambriz-Tututi suggest the use of sildenafil in combination with mepivacaine and glucose for treatment of OA in human or nonhuman mammals. It was known that horses routinely experience similar conditions that mirror human musculoskeletal injury, including OA which provide relevant clinical models for therapeutic interventions. See Cobalt, abstract. The equine models of musculoskeletal disease can provide important preclinical insights into the likely efficacy and mechanisms of activity of MSCs for the treatment of human orthopedic injuries. See abstract. A person of ordinary skill in the art (POSA) would have found it obvious to use the combination of sildenafil, mepivacaine and glucose for treating OA in a horse because the combination of sildenafil, mepivacaine and glucose for treating OA is suggested by Jahangiri, Migliore, Bernstein and Ambriz-Tututi because of the established similarity between horse and human OA and the recognized use of horses as clinically relevant models for musculoskeletal disease. The POSA would have had a reasonable expectation that treatment for OA in humans and nonhuman mammals would likewise be effective in horses.
Claim 24 depend from Claim 14, wherein the glucose is administered in a dose of from 150 mg to 400 mg and the mepivacaine is administered in a dose of from 5-30 mg. Claim 34 limits Claim 14, wherein the sildenafil is administered in a dose of from 0.01-0.1 mg with 5-20 mg mepivacaine and 10-1000 mg glucose. While Bernstein teaches depending on the formulation, it is expected that the active agent will comprise 1-99% of the composition and carrier will constitute 1-99% of the composition. Such pharmaceutical compositions may include any suitable pharmaceutically acceptable additives or adjuncts to the extent that they do not hinder or interfere with the desired therapeutic effect of the medication. See Bernstein 0018. Those of ordinary skill in the art will recognize that the exact dosage of the medication to be administered may vary depending on factors such as the age, gender, weight and health status of the individual patient, as well as on the precise nature of the condition being treated. Similarly, the length of duration of the treatment with the medication will vary from patient to patient, and will depend on the application of the medication. In all cases, the amount of medication to be administered and the precise treatment protocol should be determined by a skilled practitioner such as a physician. See Id. The preferred dosage of medication required to practice methods of the present invention, i.e., the quantity sufficient to carry out the method, is about the same as or less than that which is normally or typically administered for previously known uses or applications of the medication. Therefore, it is clear that OA treatment consists of optimizing the dose amount as well as the dose timing of the active agents. And given that the treatment can be provided several administration routes and provided to humans and animals, one of ordinary skill in the art would have reasonably understood that the dose and timing including number of times a day can be optimized depending on several different factors, (e.g., dosage formulation, weight, nature of the condition, health status, the type of mammal treated, etc.). Therefore, one of ordinary skill in the art would have found it obvious to administer the active agents at the claimed amounts and times. Since there is no evidence of the criticality of these concentrations and dosing, their difference from the prior art is not enough to render the claims patentable over the prior art.
Claim 35 limits claim 14, wherein the sildenafil, mepivacaine, and glucose are administered together at least twice with an interval of 5 to 30 days between each injection. Claim 36 limits claim 14, wherein the sildenafil, mepivacaine, and glucose are administered together at least three times with an interval of 5 to 30 days between each injection. Jahangiri teaches treatment of OA by administering the treatment composition monthly for 3 months. See abstract. That is, the composition was administered 3 times with 30-day intervals between each administration. This meets the “at least twice” (Claim 35) and “at least three times” with 30 days between each injection.
Response to arguments
Applicant's arguments have been fully considered but have not been found to be persuasive.
Applicant’s arguments that Bernstein fails to teach the current dose range of 0.01-0.1 mg sildenafil and that Janssen Pharm., Inc. v. Teva Pharm. certain contextual characteristics can make the presumption inapplicable, such as a very wide prior-art range., Inc. are not persuasive. While Bernstein teaches 50 mg or less, it is not relied upon alone for addressing the claimed dose range. The current dose range is met by the Ambriz-Tututi reference’s teachings of 0.05-0.2 mg – specifically disclosing 0.5, 1.0 and 0.2 mg – sildenafil produces dose-related antinociception.
Applicant’s arguments regarding the alleged unconventional mechanism of the claimed low-dose sildenafil are not persuasive. The claims require administration of the recited amounts for treatment of OA and do not require sildenafil to act through inhibition of intracellular calcium signaling rather than its conventionally recognized PDE5 activity. Moreover, patentability cannot be predicated upon a mechanism that is not required by the claims where the prior art otherwise suggests the claimed treatment. A POSA may find it obvious to practice the claimed invention for a different reason than Applicant.
Applicant primarily argues that the cited references do not expressly teach the exact claimed combination of sildenafil, mepivacaine, and glucose administered intra-articularly to a horse at the claimed doses and intervals. This is not persuasive because obviousness does not require express disclosure of the particular claimed combination. The rejection properly relies on the combined teachings of Jahangiri, Migliore, Bernstein, and Cobalt, which together teach intra-articular administration of glucose and local anesthetics for osteoarthritis (OA), use of mepivacaine as a known intra-articular anesthetic for OA, and administration of sildenafil (PDE5 inhibitor) for musculoskeletal conditions in mammals. A POSA would have sought to combine these known therapeutic effects.
Therefore, the rejection is deemed to still be proper and is, therefore, maintained.
Conclusion
No claims are allowed.
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/CHRIS E SIMMONS/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
