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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114 was filed in this application after appeal to the Patent Trial and Appeal Board, but prior to a decision on the appeal. 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examination under 37 CFR 1.114 and the fee set forth in 37 CFR 1.17(e) has been timely paid, the appeal has been withdrawn pursuant to 37 CFR 1.114 and prosecution in this application has been reopened pursuant to 37 CFR 1.114. Applicant’s submission filed on December 11, 2025 has been entered.
Election/Restrictions
Upon further consideration, Examiner withdraws the species election requirement (A)-(D) as set forth in the Office action mailed on 05/07/2024. Claims 4, 8-12, 16-19, and 23-26 are hereby rejoined and fully examined for patentability. In view of the withdrawal of the restriction requirement, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application.
Claim Status
Claim listing filed on December 11, 2025 is pending. Claims 2 and 21 are canceled. Claims 1, 3-6, 9, 11, 15, and 25 are amended. Claims 1, 3-20, and 22-27 are examined upon their merits.
Withdrawn Claim Rejections
The rejection of Claims 1 and 22 under 35 U.S.C. 103 as being unpatentable over Yuan 1 and Yuan 2 in view of Grumolato is withdrawn in view of Applicant’s remarks and Declaration filed on 12/11/2025. Specifically, Declaration paragraph 9 argues that in different cellular contexts, the expression levels and functions of ROR1 and ROR2 can differ and there is no support in Grumolato that Wnt5a activates ROR1 by the same mechanism as that of ROR2 in eye tissue or in a glaucoma context. This argument is persuasive because Grumolato teaches the relationship between Wnt5a and ROR1 in breast cancer cell lines (Figs. 5A-C) and in rat fibroblast cells wherein ROR1 is transfected (Figs. 5D-E). Neither of these cell models represent Wnt5a and ROR1 in eye tissue and/or glaucoma disease context. Further, Borras et al. Exp Eye Res 2006 (of record) teaches that ROR1 expression is downregulated in human trabecular meshwork cells that overexpress TIGR/MYOC to mimic a glaucoma disease state (Table 1 and abstract). This data from Borras teaches away from therapeutically inhibiting ROR1 since expression is known to be downregulated in a glaucoma model as compared to wild-type expression. Characterization of the relationship between Wnt5a and ROR1, FZD2, or FZD5 in eye tissue and/or glaucoma disease context was unknown prior to the time of filing. Even though inhibition of ROR2 and frizzled related protein-1 were known to treat glaucoma or lower pathogenic intraocular pressure (of record in Yuan 1 and Clark respectively), inhibiting ROR1, FZD2, or FZD5 is not obvious as the relationship between these receptors and Wnt5a is not characterized specifically in the context of eye tissue and/or glaucoma disease. Even if Wnt5a was assumed to bind ROR1, FZD2, or FZD5 in eye tissue and/or glaucoma disease context, it could not be reasonably predicted that the downstream signaling cascade would be similar to that of ROR2 or frizzled related protein-1 as these are structurally and functionally different receptors.
The rejection of Claims 1, 3, 5, 6, 7, 13, 15, 20, 22, and 27 under 35 U.S.C. 103 as being unpatentable over Yuan 1 and Yuan 2 in view of Grumolato and further in view of Clark is withdrawn because Clark does not overcome the deficiencies of Grumolato as described above.
The rejection of Claims 1, 3, 5, 6, 7, 13, 14-15, 20, 22, and 27 under 35 U.S.C. 103 as being unpatentable over Yuan 1 and Yuan 2 in view of Grumolato in view of Clark and further in view of Tyner is withdrawn because Tyner does not overcome the deficiencies of Grumolato as described above.
Specification (New)
The disclosure is objected to because of the following informalities:
In paragraph [006], line 5, “RoR1” should recite “ROR1” with the “O” capitalized.
In paragraph [043], line 10, “wnt5a” should recite “Wnt5a” wherein the “W” is capitalized.
In paragraphs [087]-[088], “Rcombinant” should recite “Recombinant.”
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Specifically, there is a hyperlink in paragraph [068]. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Appropriate correction is required. Applicant is urged to carefully review the specification for additional informalities.
Claim Objections (New)
Claims 1 and 14 are objected to because of the following informalities:
In Claim 1, “(ROR1)” should be on the same line as “Orphan Receptor 1.”
In Claim 14, “SEQ ID NO: 3-8” should recite “SEQ ID NOs: 3-8” to be plural.
Appropriate correction is required.
Claim Rejections - 35 USC § 112 (New)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 1, 3, 5-7, 15, 22-24, and 26 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “an inhibitor of a Wnt receptor.” Claims 3, 5-7, 15, 22-24, and 26 are dependent on Claim 1 and do not further define the claimed inhibitor. This phrase is considered functional language because the feature (the inhibitor) is defined by what it does (inhibits a Wnt receptor) rather than by what it is (MPEP § 2173.05(g)). To determine if functional language is ambiguous, the following factors are considered: (1) whether there is a clear cut indication of the scope of the subject matter covered by the claim; (2) whether the language sets forth well-defined boundaries of the invention or only states a problem solved or a result obtained; and (3) whether one of ordinary skill in the art would know from the claim terms what structure or steps are encompassed by the claim. These factors are examples of points to be considered when determining whether language is ambiguous and are not intended to be all inclusive or limiting (MPEP § 2173.05(g)). The specification teaches non-limiting examples wherein the inhibitor, in some embodiments, could comprise siRNA, an antibody, a small interfering peptide, a small molecule inhibitor, etc (paragraphs [012]-[014]). However, these exemplary embodiments are non-limiting in structure. The inhibitors are solely defined by a result obtained (i.e. comprising any structure as long as a Wnt receptor is inhibited), and the metes about bounds of these inhibitors cannot be readily determined. Therefore, Claims 1, 3, 5-7, 15, 22-24, and 26 are rejected as being indefinite.
Claims 3 and 26 perpetuate the indefinite functional language by reciting “the inhibitor inhibits Wnt receptor expression through a genetic manipulation wherein the genetic manipulation is CRISPR gene editing.” This phrase is considered functional language because the feature (the inhibitor) is defined by what it does (inhibits a Wnt receptor through a genetic manipulation) rather than by what it is (MPEP § 2173.05(g)). CRISPR gene editing is a general methodology and does not provide structural metes and bounds for the recited inhibitor.
Claim 15 perpetuates the indefinite functional language by reciting “a second, different inhibitor that is an inhibitor of an ocular Wnt5a effector.” This phrase is considered functional language because the feature (the second inhibitor) is defined by what it does (inhibits an ocular Wnt5a effector) rather than by what it is (MPEP § 2173.05(g)). For the same reasons outlined above directed to the first inhibitor, the second inhibitor is solely defined by a result obtained without any structural metes and bounds.
Note, “treating” as recited in Claim 1 is not defined in the specification and is interpreted as alleviating the symptoms or complications of an established disease, delaying the progression of an established disease, and/or curing or eliminating an established disease. “Lowering” as recited in Claim 1 is not defined in the specification and is interpreted as any decrease (significant or non-significant change) in pathogenic intraocular pressure measured by any means known in the art prior to filing.
Note, “the inhibitor inhibits Wnt receptor expression through a genetic manipulation wherein the genetic manipulation is siRNA” as recited in Claims 3 and 27 is interpreted wherein the inhibitor comprises siRNA which provides sufficient structure for the recited function.
Note, Claim 15 recites “an ocular Wnt5a effector” which is interpreted as the closed list consisting of FZD2, FZD5, ROR1, PLCB1, PPP3R1, NFATC3, and CAMK2D as defined in specification paragraphs [011] and [020].
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, 3-8, 10-11, 13, 15-16, 18, 20, and 22-27 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 claims contain 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 is directed to an inhibitor that can comprise any structure as long as the inhibitor functionally inhibits FZD2, FZD5, or ROR1 directly or indirectly. Depending claims recite wherein the inhibitor can comprise any CRISPR gene editing tool, any siRNA, any antibody, any small interfering peptide, or any small molecule inhibitor (Claims 3-4, 8, 13, and 25-27). Claims 10-11 recite wherein the inhibitor is a Wnt receptor specific small molecule selected from compounds #1-331. Claim 15 recites a second inhibitor that can comprise any structure as long as the inhibitor functionally inhibits FZD2, FZD5, ROR1, PLCB1, PPP3R1, NFATC3, or CAMK2D (see claim interpretation under 112(b) above). Therefore, the claims are directed to a genus of inhibitors. The inhibitors are required to have two functions: (1) inhibit FZD2, FZD5, or ROR1 directly or indirectly and (2) treat glaucoma or lower pathogenic intraocular pressure (Claim 1).
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant has possession of and what Applicant is claiming. In order to provide adequate written description and evidence of possession of this claimed genus of inhibitors, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof.
In the instant case, the specification teaches lowering intraocular pressure in mice and/or rabbits by administering: FZD5, FZD2, or ROR1 specific siRNA obtained commercially from ThermoFisher Scientific comprising SEQ ID NOs: 3-8 (paragraph [054] and Table 1); the anti-FZD5 antibody OMP18R5, the anti-FZD2 antibody ab52565, or the anti-ROR1 antibody cirmtuzumab (paragraph [057]); and the small molecule ROR1 inhibitor KAN0439834 (paragraph [059]). The inhibitors were administered via subconjunctival injection or eye drops (paragraphs [054]-[059]).
However, six species of siRNA, three species of antibody, and one species of small molecule inhibitor is not sufficient to describe the genus of inhibitors encompassed by the claims. A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (MPEP § 2163.05.Ib). In the absence of sufficient recitation of distinguishing identifying characteristics or structure-to-function attributes for the entire genus of inhibitors, the specification does not provide adequate written description of the claimed genus.
In re Xencor, Inc., No. 24-1870 (Fed. Cir. Mar. 13, 2025), it was decided that a claim directed to a method of treating by administering an anti-C5 antibody lacked sufficient written description because the specification did not provide a representative number of species to sufficiently support the broad genus of anti-C5 antibodies being claimed (page 6). The specification only disclosed one anti-C5 antibody, which was found insufficient given the “various specificities and epitopes” of the genus (page 6). The case law supports the lack of written description for the instantly claimed genus of inhibitors and further for the claim language reciting “Wnt receptor specific antibody” and “anti-FZD2 antibody” in Claims 8 and 25. Specifically pertaining to antibodies, it is understood that hundreds of different CDR sequences can bind an antigen with varying degrees of affinity. In light of this variability, the specification does not adequately describe what antibody structures are required to effectively bind the Wnt receptors and treat glaucoma or lower pathogenic intraocular pressure.
Therefore, in view of the case law directed to an appropriate number of representative species and proper written description of antibodies, claims 1, 3-8, 10-11, 13, 15-16, 18, 20, and 22-27 are rejected for insufficient written description.
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Claims 1, 3-8, 10-11, 13, 15-16, 18, 20, and 22-27 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 the specific species of inhibitors comprising SEQ ID NOs: 3-8 (Claim 14), the anti-ROR1 antibody cirmtuzumab (Claim 9); and the small molecule ROR1 inhibitor KAN0439834 (Claim 12), does not reasonably provide enablement for the genus of inhibitors that inhibit FZD2, FZD5, or ROR1 directly or indirectly (Claims 1, 3-8, 10-11, 13, 15-16, 18, 20, and 22-27). 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.
MPEP § 2164.01(a) states that there are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure
does not satisfy the enablement requirement and whether any necessary experimentation is “undue”. These factors 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, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The breadth of the claims and nature of the invention:
The nature of the invention is complex. As understood with the broadest reasonable interpretation, the claims are directed to an inhibitor that can comprise any structure as long as the inhibitor functionally inhibits FZD2, FZD5, or ROR1 directly or indirectly (Claim 1). Depending claims recite wherein the inhibitor can comprise any CRISPR gene editing tool, any siRNA, any antibody, any small interfering peptide, or any small molecule inhibitor (Claims 3-4, 8, 13, and 25-27). Claims 10-11 recite wherein the inhibitor is a Wnt receptor specific small molecule selected from compounds #1-331. Claim 15 recites a second inhibitor that can comprise any structure as long as the inhibitor functionally inhibits FZD2, FZD5, ROR1, PLCB1, PPP3R1, NFATC3, or CAMK2D (see claim interpretation under 112(b) above). Therefore, the claims are directed to a genus of inhibitors. The inhibitors are required to have two functions: (1) inhibit FZD2, FZD5, or ROR1 directly or indirectly and (2) treat glaucoma or lower pathogenic intraocular pressure (Claim 1).
When analyzing the scope of enablement, the claims are analyzed with respect to the teachings of the specification and are to be "given their broadest reasonable interpretation consistent with the specification." See MPEP 2111 [R-5]; Phillips v. AWH Corp., 415 F.3d 1303, 75 USPQ2d 1321 (Fed. Cir. 2005); and In re Hyatt, 211 F.3d 1367, 1372, 54 USPQ2d 1664, 1667 (Fed. Cir. 2000). Applicant always has the opportunity to amend the claims during prosecution, and broad interpretation by the examiner reduces the possibility that the claim, once issued, will be interpreted more broadly than is justified. In re Prater, 415 F.2d 1393, 1404-05, 162 USPQ 541, 550- 51 (CCPA 1969).
The state of the prior art and level of predictability in the art:
The level of predictability in the art depends, most importantly, on whether the claimed invention can be practiced by one of ordinary skill in the art. In AMGEN INC. ET AL. v. SANOFI ET AL. (No. 21-757, decided May 18, 2023), the Supreme Court held that Amgen was not enabled for “the entire genus” of antibodies that (1) “bind to specific amino acid residues on PCSK9,” and (2) “block PCSK9 from binding to [LDL receptors]” (872 F. 3d 1367, 1372) even though Amgen identified the amino acid sequences of 26 antibodies that perform these two functions. The case law applies to the instant claims which encompass a genus of inhibitors that inhibit FZD2, FZD5, or ROR1 directly or indirectly which comprises both binding and blocking functions, yet the inventors have only disclosed 10 species that are capable of the required functions (paragraphs [054]-[059]).
In Amgen, the Supreme Court has stated that despite recent advances, aspects of antibody science remain unpredictable. For example, scientists understand that changing even one amino acid in the sequence can alter an antibody's structure and function. See id., at 14. But scientists cannot always accurately predict exactly how trading one amino acid for another will affect an antibody's structure and function. Ibid. The unpredictability of polypeptide structure and function applies to the instantly claimed antibodies and extends to the other types of inhibitors claimed (e.g. small interfering peptides, siRNAs, small molecule inhibitors).
The case law shows a continued lack of predictability even after the effective filing date of the instant invention, and there is no support in the Applicant’s disclosure leading one of ordinary skill to overcome the lack of predictability in the genus of inhibitors claimed. The specification provides no guidance or direction for structure that must be maintained such that the functional properties of the invention are preserved ((1) inhibiting FZD2, FZD5, or ROR1 directly or indirectly and (2) treating glaucoma or lowering pathogenic intraocular pressure).
Level of skill in the art:
The level of skill would be high encompassing protein science, antibodies, inhibition assays, ocular treatment, etc.
Amount of direction provided by inventor and the existence of working examples:
The specification teaches lowering intraocular pressure in mice and/or rabbits by administering: FZD5, FZD2, or ROR1 specific siRNA obtained commercially from ThermoFisher Scientific comprising SEQ ID NOs: 3-8 (paragraph [054] and Table 1); the anti-FZD5 antibody OMP18R5, the anti-FZD2 antibody ab52565, or the anti-ROR1 antibody cirmtuzumab (paragraph [057]); and the small molecule ROR1 inhibitor KAN0439834 (paragraph [059]). The inhibitors were administered via subconjunctival injection or eye drops (paragraphs [054]-[059]).
However, six species of siRNA, three species of antibody, and one species of small molecule inhibitor do not adequately represent the scope of inhibitors claimed that encompasses thousands of variations. The specification provides no working examples of CRISPR gene editing, small interfering peptides, or inhibitors that indirectly inhibit the function of Wnt receptors by targeting molecules upstream or downstream in the signaling pathway. Table 2 lists 331 previously published ROR1 small molecule inhibitors but no data is provided showing functional binding affinities, glaucoma treating properties, intraocular pressure lowering properties, or evidence that the inhibitors are functional when topically administered to the eye (i.e. the inhibitors do not require metabolic conversion). A person having ordinary skill in the art would have to make a substantial inventive contribution in order to make and characterize a representative number of inhibitors and use them in the claimed method of treating in order to practice the invention with a reasonable expectation of success.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure:
In light of the unpredictability surrounding the claimed subject matter, the undue breadth of the claimed invention’s intended use, and the lack of adequate guidance, one wishing to make and practice the presently claimed invention would be unable to do so without engaging in undue experimentation. Given that the nature of the claims is in vivo treatment, a person having ordinary skill in the art would have to perform multiple further experiments, in human clinical trials or in animal models, that are predictive of treatment by administering a representative number of inhibitors in order to demonstrate the invention could be used with a reasonable expectation of success. The amount of experimentation required for enabling guidance, commensurate in scope with what is claimed, goes beyond what is considered ‘routine' within the art, and constitutes undue further experimentation in order to make the genus of inhibitors and use them in the claimed method of treatment with a reasonable expectation of success.
The instant specification does not enable the invention to make and use the entire genus of inhibitors that inhibit FZD2, FZD5, or ROR1; therefore, Claims 1, 3-8, 10-11, 13, 15-16, 18, 20, and 22-27 are rejected.
Allowable Subject Matter
Claims 9, 12, 14, 17, and 19 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.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARAH COOPER PATTERSON whose telephone number is (703)756-1991. The examiner can normally be reached Monday - Friday 8:00am - 6:00pm EST.
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/SARAH COOPER PATTERSON/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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