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, 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 04/28/2026 has been entered.
Claims 1, 5, 7 and 11 are amended and claim 10 is canceled. Claims 1-9 and 11-16 are under examination.
Rejections Withdrawn
Any previous rejections over claim 10 are hereby withdrawn in response to Applicant’s cancelation of that claim.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Rejections - 35 USC § 103
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.
The following rejections under 35 U.S.C. 103 are withdrawn in response to Applicant’s amendment and upon further consideration. The primary reference by Trese and colleagues does not disclose or suggest nerve regeneration.
Claims 1-3, 5-9, 11, 12, 15 and 16 as being unpatentable over Trese et al. (US 2016/0355559) in view of Leopold et al. (Scientific Reports, 2017; 7: 14274; pages 1-15).
The rejection of claim 4 under 35 U.S.C. 103 as being unpatentable over Trese et al. (US 2016/0355559) in view of Leopold et al. (Scientific Reports, 2017; 7: 14274; pages 1-15) as applied to claims 1-3, 5-9, 11, 12, 15 and 16 above, and further in view of Renner et al. (Front. Cell. Neurosci. (2017) 11: 254).
The rejection of claims 13 and 14 under 35 U.S.C. 103 as being unpatentable over Trese et al. (US 2016/0355559) in view of Leopold et al. (Scientific Reports, 2017; 7: 14274; pages 1-15) as applied to claims 1-3, 5-9, 11, 12, 15 and 16 above, and further in view of Zhang et al. (WO 2018/140821).
Double Patenting
The following rejections on the ground of nonstatutory double patenting are withdrawn in response to Applicant’s amendment and upon further consideration. The reference patents do not teach or suggest nerve regeneration.
The rejection of claims 1-9 and 11-16 as being unpatentable over claims 1-13 of U.S. Patent No. 10,703,787 in view of Leopold et al. (Scientific Reports, 2017; 7: 14274; pages 1-15), Renner et al. (Front. Cell. Neurosci. (2017) 11: 254) and Zhang et al. (WO 2018/140821).
The rejection of claims 1-9 and 11-16 as being unpatentable over claims 1-13 of U.S. Patent No. 10,202,429 in view of Leopold et al. (Scientific Reports, 2017; 7: 14274; pages 1-15), Renner et al. (Front. Cell. Neurosci. (2017) 11: 254) and Zhang et al. (WO 2018/140821).
The rejection of claims 1-3, 7-9, 11 and 13-16 as being unpatentable over claims 1-9 of U.S. Patent No. 10,669,321 in view of in view of Leopold et al. (Scientific Reports, 2017; 7: 14274; pages 1-15) and Zhang et al. (WO 2018/140821).
In addition, the provisional rejection of claims 1-9 and 11-16 as being unpatentable over claims 1-8, 11-14, 16-20 and 24-26 of copending Application No. 17/910,467 in view of in view of Leopold et al. (Scientific Reports, 2017; 7: 14274; pages 1-15), Renner et al. (Front. Cell. Neurosci. (2017) 11: 254) and Zhang et al. (WO 2018/140821) is withdrawn in response to the abandonment of that application.
New Objections/Rejections
Specification
The specification is objected to as failing to provide proper antecedent basis for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o). Correction of the following is required. Claims 1 and 7 are amended to recite a “norrin mutant having at least 85% amino acid identity to SEQ ID NO: 2” and “said norrin mutant is a fragment of SEQ ID NO: 2”, respectively. The instant specification only defines a norrin mutant having 85% amino acid identity to SEQ ID NO: 1.
Claim Objections
Claim 1 is objected to because of the following informalities. Claim 1 recites “the N-terminus cleavage fragment being of up to 40 amino acid residues less than the native norrin protein”, which is grammatically awkward. Generally, when referring to countable nouns, for instance, “amino acid residues”, the adjective “fewer” should be used. The following amendment is suggested: “the N-terminus cleavage fragment having up to 40 fewer amino acid residues
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-9 and 11-16 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.
Amended claim 1 defines two types of N-terminus norrin truncates capable of binding to nerve cells in the situs in lines 5-9, namely (1) an N-terminus cleavage fragment being of up to 40 amino acid residues less than the native norrin protein and retaining a cysteine-knot motif of the native norrin protein and (2) a norrin mutant having at least 85% amino acid identity to SEQ ID NO: 2 and retaining a cysteine-knot motif of the native norrin protein. The recitation of “an N-terminus cleavage fragment or mutant relative to a native norrin protein” in line 4 immediately preceding this is confusing because it is not clear if the mutant in line 4 refers to a separate type of norrin mutant or to the mutant having 85% identity to SEQ ID NO: 2.
The final step of claim 1 recites:
allowing sufficient time for said N-terminus norrin truncate or said norrin mutant to selectively up-regulate gene expression of at least one of leucine-rich repeat containing G-protein coupled receptor (LGR) 4 (LGR4), LGR5, LGR6, or a combination thereof and activate a Wnt signaling pathway, to regenerate nerves in the situs of the living subject and associated with inherited vitreoretinopathies, retinopathy of prematurity, diabetic retinopathy, retinal artery and vein occlusions, inner ear hair loss, and cochlear abnormalities.
It is not clear what the phrase “and associated with inherited vitreoretinopathies, retinopathy of prematurity, diabetic retinopathy, retinal artery and vein occlusions, inner ear hair loss, and cochlear abnormalities” at the end of the clause is referring to. For instance, are the living subjects suffering from one of these conditions, or do they merely illustrate the types of conditions they may require nerve regeneration?
Claims 2-9 and 11-16 are included in this rejection for depending upon rejected claims without resolving the indefiniteness with regard to the additional mutant.
Claim Rejections - 35 USC § 112(a)
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.
New Matter
Claims 1-3, 7-9 and 11-16 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 inventors, at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
Claim 1 has been amended to recite “a norrin mutant having at least 85% amino acid identity to SEQ ID NO. 2” in lines 7-8, which represents new matter. In addition, claim 7 has been amended to recite said norrin truncate or norrin mutant is a fragment of SEQ ID NO: 2 that binds a frizzled-4 receptor of the nerve cells in the ear. In the original claim set filed 07/11/2022, claim 7 recited the truncate/mutant is a fragment of SEQ ID NO: 1.
The instant specification discloses a paragraph [0009]: “a norrin mutant having at least 85% amino acid identity to SEQ ID NO. 1”. SEQ ID NO: 1 is the human precursor sequence (133 amino acids), while SEQ ID NO: 2 is the mature form of this protein (109 amino acids). Applicant points to paragraphs [0064] and [0122] of the instant specification as supporting the amendments, however, these passages do not disclose the amendments to claims 1 and 7. Applicant also points to now canceled claim 10 as providing support for the amendments. Former claim 10 depended from claim 1 and recited “wherein said N-terminus norrin truncate consists of a polypeptide of SEQ ID NO: 2”. This claim limited the norrin truncate having up to 40 fewer amino acids than the native norrin protein to the sequence consisting of SEQ ID NO: 2. The transitional phrase “consisting of” excludes any element, step, or ingredient not specified in the claim (see MPEP 2111.03), thus cannot provide support for expanding the limitation from 85% sequence identity of SEQ ID NO: 1 to include 85% sequence identity to SEQ ID NO: 2 or reciting the truncate/mutant is a fragment of SEQ ID NO: 2. In summary, there is no explicit, implicit or inherent support for these claim amendments.
Written Description
Claims 1-3, 7-9 and 11-16 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 inventors, at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
The claims are drawn to a method of nerve regeneration in a living subject at a situs comprising administering an N-terminus cleavage mutant relative to a native norrin protein. To provide evidence of possession of a claimed genus, 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 deciding whether the application complies with the written description requirement of 35 USC 112(a) or 35 USC 112 (pre-AIA ), first paragraph, it is necessary to understand what Applicant is claiming (see above) and what Applicant has possession of. From the specification, it is clear that Applicant has possession of the norrin truncate SEQ ID NO: 2, which is a 24 residue N-terminus norrin truncate and the mutants set forth in SEQ ID NOs: 3-21 (see paragraphs [0061] and [0064]). Further, this passage discloses a norrin mutant that is a truncate having the sequence set forth in SEQ ID NO: 2 with one or more mutations at positions 84-88 relative to SEQ ID NO: 1, which interferes with protease cleavage, thereby increasing biological half-life. According to US Patent 10,799,557, there is also possession of (1) an N-terminus norrin truncate having a polypeptide N-terminus cleavage relative to a native norrin protein of a maximum of 40 amino acid residues and retaining a cysteine-knot motif of the native norrin, or (2) a norrin mutant that has at least 85% amino acid identity to SEQ ID NO: 1 and retains the cysteine-knot motif of the native norrin (see claim 1). The specification does not provide support, however, for a mutant falling outside of these limitations, such as the cleavage mutant in line 4 of claim 1 or for a norrin mutant that has at least 85% amino acid identity to SEQ ID NO: 2.
The specification requires that the norrin variants of the invention have the ability to bind the frizzled-4, LGR4, LGR5 and LGR6 receptors of ear and retinal nerve cells (see paragraph [0046]). The genus of cleavage mutants as set forth in the amended claims also require the ability to regenerate nerves. While the specification provides multiple species of norrin mutants (SEQ ID NOs: 3-21), these all differ from instant SEQ ID NO: 1 by a single amino acid, and therefore these species are not representative of the genus of undefined norrin mutants. In addition, the truncation mutant, SEQ ID NO: 2, differs from SEQ ID NO: 1 by about 85% overall, however, there are no examples of mutants having only 85% identity to SEQ ID NO: 2 while retaining the required functions. In this case, the only factor present in the claim is a partial structure in the form of a recitation of percent identity. There is not even identification of any particular portion of SEQ ID NO: 2 that must be conserved while preserving the required functions. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116). Applicant has possession of:
The norrin truncate set forth in SEQ ID NO: 2;
The norrin mutants set forth in SEQ ID NOs: 3-21;
A norrin mutant having the sequence set forth in SEQ ID NO: 2 with one or more mutations at positions 84-88 relative to SEQ ID NO: 1;
An N-terminus norrin truncate having a polypeptide N-terminus cleavage; relative to a native norrin protein of a maximum of 40 amino acid residues, or
A norrin mutant that has at least 85% amino acid identity to SEQ ID NO: 1.
However, the skilled artisan cannot envision the detailed chemical structure of the encompassed mutants falling outside these limitations and mutants having 85% sequence identity to SEQ ID NO: 2; therefore, conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence. Therefore, only isolated polypeptides as listed above in 1-5, but not the full breadth of the claim meets the written description provision of 35 U.S.C. §112, first paragraph. 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).
Scope of Enablement
Claims 1-4, 7-9 and 11-16 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification is enabling for stimulating nerve regeneration in ear and retinal nerve cells in a subject comprising administering to said subject a norrin truncate or a norrin mutant, wherein:
The norrin truncate is set forth in SEQ ID NO: 2;
The norrin mutants are set forth in SEQ ID NOs: 3-21;
A norrin mutant is set forth in SEQ ID NO: 2 with one or more mutations at positions 84-88 relative to SEQ ID NO: 1;
An N-terminus norrin truncate having a polypeptide N-terminus cleavage relative to a native norrin protein of a maximum of 40 amino acid residues, or
A norrin mutant having at least 85% amino acid identity to SEQ ID NO: 1.
The specification does not, however, reasonably provide enablement for the claims as broadly recited. 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 or use the invention commensurate in scope with these claims.
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." (See In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 Fed. Cir. 1988) 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.
The claims are broad with respect to the recited norrin truncates and norrin mutants. The specification teaches that wild-type norrin and certain disclosed norrin truncates and mutants stimulate nerve cells in the ear and eye. For example, the K86P norrin mutant “stimulates differentiation and survival of resident stem cells” (see paragraph [0105] of the PGPUB). Further, the two norrin truncation mutants (mutation at position 84) result in apparent neuronal growth (see paragraph [0106] of the PGPUB). The specification discloses that “ectopic expression of norrin” results in “an increase in proliferation of retinal progenitor cells and retinal thickness in mice” (see paragraph [0109] of the PGPUB). Norrin treatment also significantly increases retinal ganglion cell (RGC) levels and density and promotes dendrite and axon growth (see paragraph [0110]-[0112]). The specification concludes (paragraph [0122]):
Based on the experimental findings presented herein, norrin may represent a unique molecule that is able to function as both a Wnt-ligand and a growth factor and regulate angiogenesis and neurogenesis in a fashion that mimics that seen in the developing eye and ear. Norrin may also stimulate regeneration of inner ear sensory hair cells and support their integration into nerve cells. This has significant implication in the treatment of many eye and ear diseases characterized by anomalous vasculature and anomalous nerve development. These conditions are seen in the inherited vitreoretinopathies, illustratively including FEVR, Norrie disease, and persistent fetal vasculature, as well as retinopathy of prematurity, diabetic retinopathy, retinal artery and vein occlusions, inner ear hair loss, and cochlear abnormalities.
The specification does not support the enablement of norrin mutant falling outside of these limitations, such as the cleavage mutant in line 4 of claim 1 or for a norrin mutant that has at least 85% amino acid identity to SEQ ID NO: 2, being capable of carrying out the claimed methods.
As noted by Applicant in the Remarks filed 04/28/2026, “nerve regeneration is a pioneering innovation” (see p. 6). In addition, Applicant asserts “[t]he unpredictability of biotech in general and neuroscience in particular, are enshrined in case law (see p. 7 of the Remarks filed 04/28/2026). Indeed, Wong (Int. J. Mol. Sci. 2022, 23, 10179. https://doi.org/10.3390/ijms231710179) teach that two years after the effective filing date of the instant application, no therapies for regenerating RGCs exist and more research is necessary (see abstract; p. 11, last paragraph). While the specification provides multiple species of norrin mutants (SEQ ID NOs: 3-21), these all differ from instant SEQ ID NO: 1 by a single amino acid. In addition, the truncation mutant, SEQ ID NO: 2, differs from SEQ ID NO: 1 by about 85% overall, however, there are no examples of mutants having only 85% identity to SEQ ID NO: 2 having the required functions. Therefore, given the complexity of nerve regeneration, the evidence presented in the specification and the art is not commensurate in scope with the breadth of the recited norrin fragments and mutants.
Due to the large quantity of experimentation necessary to develop norrin fragments and mutants capable of nerve regeneration, the lack of direction/guidance presented in the specification regarding fragments and mutants other than those disclosed in the specification, the unpredictability of neuroscience and nerve regeneration, and the breadth of the claims which fail to recite limitations on the recited norrin fragments and mutants, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention in its full scope.
Conclusion
No claim is allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Dresner et al. (US2019/0169247—on IDS filed 07/11/2022) teach a method of vascular regeneration in retinal tissue comprising: exposing the retinal tissue to a recombinant norrin truncate and allowing sufficient time for said norrin truncate in the retinal tissue to result in capillary vascular regeneration, wherein the norrin-truncate has 100% sequence identity to instant SEQ ID NO: 2 (see claims 1, 11). Dresner et al. also teach synthetic norrin retaining frizzled-4 receptor binding properties that have the same sequences as those recited in claims 5 and 6 as well as limitations of claims 11-12 (see paragraph [0053]):
A particularly well suited norrin mutant for the present invention is a truncate (SEQ ID NO. 2) with a mutation in at least one position 81-90 of SEQ ID NO: 1 that interferes with protease cleavage of the resulting protein. One or more mutations at positions 84, 85, 86, 87, and 88 SEQ ID NO: 1
Dresner et al. contemplate that the norrin-truncates may be used to treat conditions such as FEVR, Norrie disease, retinopathy of prematurity, diabetic retinopathy, and retinal artery and vein occlusions (see abstract; paragraph [0123]). While Dresner et al. recognize that norrin affects neurogenesis and angiogenesis (see paragraphs [0094]-[0095]), they do not teach or suggest a method of nerve regeneration.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA M BORGEEST whose telephone number is (571)272-4482. The examiner can normally be reached M-F 9-5:30 EDT.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached at 5712720911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/CHRISTINA M BORGEEST/Primary Examiner, Art Unit 1675
Prosecution Insights