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 .
Applicant’s election without traverse of group I and lorecivivint in the reply filed on 5/4/26 is acknowledged.
Claims 9-15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 5/4/26.
Response to Amendment
The instant amended claims do not have status identifiers, as clearly required by 37 CFR 1.121 (c): Claims. Amendments to a claim must be made by rewriting the entire claim with all changes (e.g., additions and deletions) as indicated in this subsection, except when the claim is being canceled. Each amendment document that includes a change to an existing claim, cancellation of an existing claim or addition of a new claim, must include a complete listing of all claims ever presented, including the text of all pending and withdrawn claims, in the application. The claim listing, including the text of the claims, in the amendment document will serve to replace all prior versions of the claims, in the application. In the claim listing, the status of every claim must be indicated after its claim number by using one of the following identifiers in a parenthetical expression: (Original), (Currently amended), (Canceled), (Withdrawn), (Previously presented), (New), and (Not entered).
Applicant is required to submit claims with the proper status identifiers.
Claim Objections
Claim 3 is objected to because of the following informalities: there is no comma between “lorecivivint” and “WNT974” although they are two different compounds. Appropriate correction is required.
Improper Markush Rejection
Claims 2 and 3 are rejected on the judicially-created basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature. The members of the improper Markush grouping do not share a substantial feature and/or a common use that flows from the substantial structural feature for the following reasons: Claim 2 recites the Markush group “a small molecule drug or siRNA”. The small molecule has no structural relationship to the siRNA, and so can have no substantial structural feature in common with the siRNA. Additionally, the genus of small molecules recited in instant claim 3 represent an improper Markush grouping of alternatives. Each have a different structure and distinct mechanisms of action.
Therefore, the members of the Markush group lack any common substantial structural feature that provides a common use, and the group of alternatives is an improper Markush group. In response to this rejection, Applicant should either amend the claim(s) to recite only individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims(s) in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature. This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. 134 and 37 CFR 41.31(a)(1).
However, as instantly drafted, Claim 1 link(s) the inventions of claims 2 and 3. The restriction requirement among the linked inventions is subject to the nonallowance of the linking claim(s), claim 1. Upon the allowance of the linking claim(s), the restriction requirement as to the linked inventions shall be withdrawn and any claim(s) depending from or otherwise including all the limitations of the allowable linking claim(s) will be entitled to examination in the instant application. Applicant(s) are advised that if any such claim(s) depending from or including all the limitations of the allowable linking claim(s) is/are presented in a continuation or divisional application, the claims of the continuation or divisional application may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Where a restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. In re Ziegler, 44 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
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, 2, and 5-8 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.
Instant claim 1 is directed to administration of any “Wnt pathway inhibitor”, which is a genus of agents that has not been adequately described in the specification. Although the specification discloses specific agents as recited in claim 3, the species are not representative of the entire claimed genus. The specification does not adequately describe the structure required for the function. Without further description of the structure required for the function, one would not be able to readily recognize which agents are necessarily included or excluded from the recited genus of Wnt pathway inhibitors.
Instant claim 2 requires for the Wnt pathway inhibitor to be a small molecule drug or siRNA. However, the specification does not adequately describe the structure required for the small molecule drug or siRNA to function as a Wnt pathway inhibitor and clearly not any small molecule drug or siRNA would function as a Wnt pathway inhibitor.
Claims 5-8 are rejected because they depend from claim 1 and do not obviate the rejection.
The MPEP states that for a generic claim, the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. See MPEP § 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163. Although the MPEP does not define what constitute a sufficient number of representative species, the courts have indicated what do not constitute a representative number of species to adequately describe a broad genus. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618. Additionally, in Carnegie Mellon University v. Hoffman-La Roche Inc., Nos. 07-1266, -1267 (Fed. Cir. Sept. 8, 2008), the Federal Circuit affirmed that a claim to a genus described in functional terms was not supported by the specification’s disclosure of species that were not representative of the entire genus. Furthermore, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co. the court stated:
"A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus ...") Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The claims are rejected under the written description requirement for failing to disclose adequate species to represent the claimed genus, the genus being Wnt pathway inhibitors.
The Guidelines for Examination of Patent Applications under the 35 USC § 112, first paragraph, “Written Description” Requirement”, published at Federal Register, Vol. 66, No. 4, pp. 1099-1111 outline the method of analysis of claims to determine whether adequate written description is present. The first step is to determine what the claim as a whole covers, i.e., discussion of the full scope of the claim. Second, the application should be fully reviewed to understand how applicant provides support for the claimed invention including each element and/or step, i.e., compare the scope of the claim with the scope of the description. Third, determine whether the applicant was in possession of the claimed invention as a whole at the time of filing.
Thus, having analyzed the claims with regard to the Written Description guidelines, it is clear that the specification does not disclose a representative number of species for Wnt pathway inhibitors within the instant enormous genus that function as required. Thus, one skilled in the art would be led to conclude that Applicant was not in possession of the claimed invention at the time the application was filed.
Claims 1-8 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 performing a microfracture comprising creating fractures and administering one of the agents of instant claims 3 and 4 directly via intraarticular injection to the microfracture site or in the vicinity thereof, does not reasonably provide enablement for a method of performing a microfracture comprising creating fractures and administering any Wnt pathway inhibitor via any means. 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/or use the invention commensurate in scope with these claims.
Factors to be considered in a determination of lack of enablement include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)
The instant claims are directed to a method of performing a microfracture comprising creating fractures and administering any Wnt pathway inhibitor via any means.
The specification does not draw an adequate nexus between delivery of any Wnt pathway inhibitor with a resultant enhancement of the microfracture procedure.
For example, Virk et al. (J Bone Joint Surg Am.2013;95:694-701) teach that sclerostin, a Wnt inhibitor, inhibits bone formation (page 695). Therefore, it would not have the desired effect of enhancing a microfracture procedure to repair cartilage defects.
The specification demonstrates in vitro reduction of COL1 in Wnt inhibition (Figure 1), which is not commensurate in scope with a method of performing a microfracture comprising creating fractures and administering any Wnt pathway inhibitor via any means.
The instant claims are directed to broad systemic delivery (i.e. oral delivery) of any Wnt pathway inhibitor. The in vivo experimentation of the specification is strictly prophetic. Activity in vitro is not predictable of the in vivo therapeutic effect in the in vivo complex environment. The specification is not enabling for broad systemic delivery of any Wnt pathway inhibitor with a result of effecting the microfracture procedure.
Schizas et al. (Orthopedic Reviews 2019; 11:7950, 148-153) teach delivery of adjuvant therapies with microfracture techniques and teach that in order to achieve optimal results and reach the intended purpose for a pharmaceutical or biological agent, the selection of a suitable delivery mechanism is extremely important. Moreover, a proper delivery strategy can affect the dosage and ultimately determine whether an effective pharmacokinetic profile is achieved. Techniques for the delivery of soluble reagents targeting cartilage defect treatment have evolved over the years. Simple intra-articular injections into the defect have been overshadowed by more focused delivery systems, like bulk phase scaffolds or membranes (page 150).
There is no guidance in the specification as filed that teaches how to deliver the instantly recited genus of possible agents, which encompasses agents of different structures that act via different mechanisms, and predictably impact the microfracture procedure in vivo.
It is noted that the specification is enabling for a method of performing a microfracture comprising creating fractures and administering one of the agents of instant claims 3 and 4 directly via intraarticular injection to the microfracture site or in the vicinity thereof.
As outlined above, it is well known that there is a high level of unpredictability in the art for therapeutic in vivo delivery. The scope of the claims in view of the specification as filed together do not reconcile the unpredictability in the art to enable one of skill in the art to make and/or use the claimed invention, namely a broad method of performing a microfracture procedure comprising creating fractures in subchondral bone and delivering via any means any Wnt pathway inhibitor encompassing in vivo effects.
MPEP 2164.01
Any analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention.
Also, MPEP 2164.01(a)
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Given the teachings of the specification as discussed above, one skilled in the art could not predict a priori whether introduction of any Wnt inhibitor of the instant genus in vivo by the broadly disclosed methodologies of the instantly claimed invention, would result in effect in a microfracture procedure. To practice the claimed invention, one of skill in the art would have to de novo determine; the stability of the molecule in vivo, delivery of the molecule to the whole organism, specificity to the target tissue in vivo, dosage and toxicity in vivo, and entry of the molecule into the cell in vivo and the effective action therein. Without further guidance, one of skill in the art would have to practice a substantial amount of trial and error experimentation, an amount considered undue and not routine, to practice the instantly claimed invention.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation (see MPEP 2164.01(a)).
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:
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.
Claim(s) 1-8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Schizas et al. (Orthopedic Reviews 2019; 11:7950, 148-153), in view of Ghouri et al. (Calcified Tissue International (2021) 109:339–350), and Yen et al. (Med. Sci. Sports Exerc., Vol. 40, No. 2, pp. 200–205, 2008).
Schizas et al. teach various adjuvant therapies for the enhancement of microfracture technique in cartilage repair (title, pages 149-150) (instant claim 1).
Schizas et al. teach that microfracture technique is a simple, fast and low-cost procedure targeted in inducing the intrinsic healing potential of cartilage by utilizing and stimulating the subchondral bone marrow. Schizas et al. teach that the effort to optimize the outcomes of microfracture can be pursued by either enhancing the microfracture procedure itself, or by developing adjuvant treatments (page 151).
Schizas et al. teach administration of the adjuvant therapy to the same area as the microfractures via intraarticular injection after the fractures in the subchondral bone (page 149) (instant claims 5-7).
Schizas et al. teach: Both fracture healing and endochondral bone formation are directly regulated by BMPs, fibroblast growth factor 2 (FGF-2), Wnt proteins and Wnt signaling antagonists (page 152).
Although Schizas et al. teaches adjuvant therapies for the enhancement of microfracture technique in cartilage repair in patients with osteochondral defects; and teaches that both fracture healing and endochondral bone formation are directly regulated by Wnt signaling antagonists, Schizas et al. does not teach that the adjuvant therapy is administration of a Wnt inhibitor.
However, it was known to administer lorecivivint, a Wnt pathway inhibitor, to treat osteoarthritis (OA) of the knee, as taught by Ghouri et al.
Ghouri et al. teaches: Subchondral bone plays a role in maintaining hyaline articular cartilage integrity and its pathology is integral to the OA process. A number of therapies used for osteoporosis have been explored as OA therapies, targeting altered bone turnover in the subchondral region (page 340).
Ghouri et al. teaches: Lorecivivint (formerly SM04690) is an inhibitor of the Wnt signaling pathway and also inhibits the enzymes CDC-like kinase 2 (CLK2) and dual-specificity tyrosine phosphorylation-regulated kinase 1A, enhancing chondrogenesis, chondrocyte function and reducing inflammation (page 342) (instant claims 2-4).
Ghouri et al. teaches: Medium dose (0.07 mg) Lorecivivint SM04690 did significantly improve WOMAC A1 (pain when walking on a flat surface) score versus placebo in unilateral symptomatic knee patients at 39 and 52 weeks and unilateral symptomatic patients without widespread pain at 26, 39 and 52 weeks (page 342)
Therefore, it would have been obvious for the target not only to be subchondral bone, but in the knee (instant claim 8).
Ghouri et al. teaches: A further 24-week, phase IIb study randomised 695 patients to receive a single dose lorecivivint (0.03, 0.07, 0.15 or 0.23 mg), vehicle placebo or sham (dry needle only) at baseline. 635 subjects completed the study and the pre liminary results demonstrated significant improvements from baseline in 0.07 mg and 0.23 mg lorecivivint dose groups compared to placebo for numeric rating scale pain (0.07 mg and 0.23 mg at weeks 12 and week 24), WOMAC Pain (0.07 mg at week 12; 0.23 mg at weeks 12 and 24), WOMAC Physical Function (0.07 mg at week 12; 0.23 mg at weeks 12 and 24) and patient global assessment (0.07 mg at week 12; 0.23 mg at weeks 12 and 24) [35]. In addition, a homogenous group of patients with joint space width 2–4 mm and no widespread pain demonstrated an improved symptom effect size vs placebo at 12 and 24 weeks compared to the full analysis set at 0.07 mg [36] (pages 342-343). The patients were treated via intra-articular injection [33] (instant claim 7).
Ghouri et al. teaches that lorecivivint is a knee osteoarthritis drug (page 348).
Therefore, it would have been obvious to inject lorecivivint intraarticularly into the subchondral bone (instant claims 7 and 8); and it would have been obvious to select lorecivivint as the adjuvant therapy with the microfracture technique of Schizas et al. with the expectation of enhanced microfracture technique because Schizas et al. teaches that microfracture induces the intrinsic healing potential of cartilage by utilizing and stimulating the subchondral bone marrow and that it is beneficial to incorporate an additional therapy, wherein Ghouri et al. teaches that lorecivivint treatment is used to treat osteoarthritis in knees (instant claim 1).
Additionally, microfracture was a routine treatment of osteoarthritis, as taught by Yen et al. Since it was known to combine microfracture with adjuvant therapies, as taught by Schizas et al. and it was known to utilize microfracture and lorecivivint to treat osteoarthritis, it would have been obvious to combine microfracture and lorecivivint with the motivation of enhanced treatment of osteoarthritis and a reasonable expectation of the known benefits of each.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Amy R Hudson whose telephone number is (571)272-0755. The examiner can normally be reached M-F 8:00am-6:00pm.
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/AMY ROSE HUDSON/Primary Examiner, Art Unit 1636
