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
2. Claims 1 – 9 are pending in this application. Applicant’s preliminary amendment, submitted March 4, 2024, is entered, wherein claim 3 is amended and claims 5 – 9 are new.
Claims 1 – 9 are examined on the merits herein.
Priority
3. This application is a national stage application of PCT/JP2022/033150, filed September 2, 2022, which claims benefit of foreign priority document JP2021-144702, filed September 6, 2021.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 03/05/2024 was filed 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.
Claims 6 – 9 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 a method of treating or inhibiting the progression of OA comprising administering effective dose of a G protein-coupled receptor kinase 5 inhibitor and hyaluronic acid to a human or animal patient, does not reasonably provide enablement for a method of preventing the progression of OA in a patient. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims. Claims 5 – 9 depend from claim 6.
The Applicant’s attention is drawn to re Wands, 8 USPQ2d 1400 (CAFC1988) at 1404 where the court set forth eight factors to consider where assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
(1) The nature of the invention;
(2) the state of the prior art;
(3) the relative skill of those in the art;
(4) the predictability or unpredictability of the art;
(5) the breadth of the claims;
(6) the amount of direction or guidance presented;
(7) the presence or absence of working examples; and
(8) the quantity of experimentation necessary.
The nature of the invention & The breadth of claims:
The claimed invention is directed to a method of preventing, treating, or inhibiting the progression of OA. In order to be enabled for the full scope of the method, one skilled in the art must reasonably be able to ascertain which compositions are effective to prevent OA or the progression of OA. Moreover, “preventing” OA including administering the claimed formulation to a subject not suffering from OA in such a manner that the subject does not experience OA in the future.
The state of prior art:
While there are publications that describe methods of treating OA, there is no evidence in the prior art that the claimed composition would prevent OA from ever occurring. For example, Sueishi et al. (Arthritis & Rheumatology, 2019, Vol. 72, Issue 4, page 620 – 631, Reference included with PTO-892) teach that NF-κB-dependent signaling is an important modulator in OA and G protein-coupled receptor kinase 5 (GRK5) regulates the NF-κB pathway (Abstract). Sueishi et al. treats OA-induced mice with amlexanox (page 7, para. 2) and the results suggest that GRK5 regulates cartilage degradation through a catabolic response mediated by NF-κB signaling, and is a potential target for OA treatment (Abstract). Migliore (Clinical Cases in Mineral and Bone Metabolism, 2015, Vol. 12, Issue 1, page 31 – 33, Reference included with PTO-892) discloses that hyaluronic reduces OA symptoms and structural damage (Abstract). Thus, the art recognize treatment regimens including administering amlexanox and hyaluronic acid in treating OA, but not in the prevention thereof.
The relative skill of those in the art:
The relative skill of those in the art is high.
The predictability or unpredictability of the art:
According to Chen et al., OA is the most common degenerative joint disease and a major cause of pain and disability in adult individuals. The etiology of OA includes joint injury, obesity, aging, and heredity. The wide range of etiology makes it impossible to predict which subjects will develop OA in the future and medication for OA are generally given to subjects already displaying OA symptoms rather than to healthy subjects who might develop OA in the future.
The amount of direction or guidance presented & The presence or absence of working examples:
The specification provides some directions for evaluation the effect of simultaneous administration of amlexanox and hyaluronic acid on OA-related markers and cartilage degeneration. For example, the disclosure describes an in-vitro assay using human OA cartilage cells in which amlexanox and hyaluronic acid are administered and the expression levels of IL-6, MMP13, and ADAMTS4 are measured by quantitative real-time PCR. The results show decreased expression of these inflammatory and cartilage-degradation-associated markers, and the specification characterizes the combined administration as producing a synergistic inhibitory effect (para. [0081 – 0083]). The disclosure also describes in-vivo mouse studies using surgically induced OA/DMM models, in which amlexanox and hyaluronic acid are administered intra-articularly every 5 days or every 10 days for 8 weeks, followed by safranin O staining, OARSI scoring, and pain-threshold measurements. These examples show reduced OARSI scores, inhibition of cartilage degeneration, and reduced pain in the combined-treatment groups as compared with amlexanox along or hyaluronic acid alone (para. [0084 – 0092]). However, the working examples does not provide sufficient guidance enabling the prevention of progression of OA as claimed, including across different types or stages of OA, different patient populations, different dosing regimens, and different clinical endpoints for determining prevention of disease progression. Thus, the specification does not provide adequate direction or working examples sufficient to enable the full scope of preventing progression of OA as claimed without undue experimentation.
The quantity of experimentation necessary:
In order to carry out the claimed preventative treatment, one of ordinary skill in the art would need to develop specifically preventative treatment from scratch with no assistance from Applicant’s declaration beyond the general idea that the claimed composition is capable of treating OA. Because OA is caused by multiple factors as mentioned above, determining which healthy patients would benefit from this treatment would be difficult and unpredictable based on the state of the art, and any treatment is likely to be imperfectively effective given the influence of other factors..
Genentech, 108 F.3d at 1366, states that “a patent is not a hunting license. It is not a reward for search, but 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.”
Therefore, in view of the Wands factors, as discussed above, particularly the state of art and the lack of guidance or working examples, Applicant fails to provide information sufficient to practice the claimed invention.
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 factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
i. Determining the scope and contents of the prior art.
ii. Ascertaining the differences between the prior art and the claims at issue.
iii. Resolving the level of ordinary skill in the pertinent art.
iv. 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 are rejected under 35 U.S.C. 103 as being unpatentable over Sueishi et al. (Arthritis & Rheumatology, 2019, Vol. 72, Issue 4, page 620 – 631, Reference included with PTO-892) in view of Migliore (Clinical Cases in Mineral and Bone Metabolism, 2015, Vol. 12, Issue 1, page 31 – 33, Reference included with PTO-892).
a. Sueishi et al. teach that mice with osteoarthritis (OA) are treated with intraarticular injection of amlexanox (Abstract). Thus, the teachings of Sueishi et al. read on the limitations “a G protein-coupled receptor kinase 5 inhibitor” and “animal patient” of claims 1, 4, and 6, “Amlexanox” of claims 2 and 7, “intraarticular injection” of claims 3, 5, and 8 – 9.
However, Sueishi et al. do not teach the osteoarthritis progression inhibitor or the inhibition kit comprises hyaluronic acid.
Migliore discloses the effectiveness and utility of hyaluronic acid in OA (Title). Migliore teaches that the repeated cycles of intra-articular injections of HA not only are safe and improve knee OA symptoms during the in between cycle period but also exert a marked carry-over effect for at least 1 year after the last cycle (page 33, Left Col., para. 1). Thus, the teachings of Migliore reads on the limitation “hyaluronic acid” of claims 1, 4, and 6.
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to combine amlexanox as taught by Sueishi et al. with hyaluronic acid in view of Migliore to treat OA. It would have been obvious for one of ordinary skill in the art to combine amlexanox as taught by Sueishi et al. with hyaluronic acid in view of Migliore to treat OA because both amlexanox and hyaluronic acid are known separately in the prior art for the purpose of treating OA, and it would have been obvious to combine them to treat the same disease. One of ordinary skill in the art would have had a reasonable expectation of success to combine amlexanox as taught by Sueishi et al. with hyaluronic acid in view of Migliore because it is well known to combine drugs to treat the same disease.
Moreover, the specification has also been considered for support of unexpected results and comparative data concerning the simultaneous administration of amlexanox and hyaluronic acid. The disclosure includes comparative testing against hyaluronic acid alone and amlexanox alone. For example, Example 1 and Figure 1 show decreased expression of IL-6, MMP13, and ADAMTS4 in human OA cartilage cells treated with the combination (para. [0080 – 0083]), and Examples 2 and 3 and Figures 2C and 3C show reduced OARSI scores in surgically induced OA mouse models treated intra-articularly with the combination as compared with the individual components (para. [0084 – 0092]). Figure 3D further shows an increased withdrawal threshold for the combination as compared with amlexanox alone. These comparative data have been considered and may support an improved or synergistic effect for the specifically tested composition comprising amlexanox and hyaluronic acid under the disclosed concentrations, route of administration, dosing intervals, and experimental models. However, claim 1 is not limited to amlexanox, but broadly recites a composition comprising a G protein-coupled receptor kinase 5 inhibitor and hyaluronic acid. The specification does not provide comparative data, working examples, representative species, or structure-function guidance sufficient to show that GRK5 inhibitors generally, when combined with hyaluronic acid, would exhibit the alleged synergistic effect. The examples are limited to one GRK5 inhibitor, amlexanox, and do not establish that the full genus of GRK5 inhibitors would behave similarly in the claimed composition. Furthermore, the comparative data are limited to specific concentration of amlexanox and hyaluronic acid. The data do not reasonably establish that the full scope of claimed method prevents or inhibits progression of OA across the breadth of the claims. Accordingly, the specification has been considered for unexpected or synergistic results, however, the results are not commensurate in scope with the broadly claimed composition and method.
Conclusion
No claim is found to be allowable.
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/H.Y.L./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693
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