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 .
Status of Application/Amendments/Claims/RCE 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1.114 and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicants’ submission filed on 3/30/2026 has been considered.
The declaration submitted on 3/30/2026 by Dr. Weldon Haw was received and fully considered. Briefly, the declaration argues that HSV infection of the eye is a major cause of neurotrophic keratitis and therefore one of ordinary skill would be deterred from using such a vector for delivering bNGF. Furthermore, the declaration points to Fig 1 of Exhibit A which shows a comparison of total human NGF post-single HSV-bNGF or six-time rh-NGF topical administration to wound corneas.
Claims 33 and 34 are newly added. Claims 31 and 32 are canceled. Claim 21 has been amended. Claims 1-5, 7, 10-11, 15-21, 24-30 and 33-34 are pending. Claims 1-5 are currently withdrawn from further consideration pursuant to 37 CFR 1.142 (b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 7, 10-11, 15-21, 24-30 and 33-34 are the subject of the present Official action. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
Applicant’s claim for the benefit of a prior-filed application PRO 63/459,102, PRO 63/460,948, PRO 63/593,085 and DIV of 10/634,382 filed on 4/13/2023, 4/21/2023, 10/25/2023 and 4/12/2024, respectively, under 35 U.S.C 119(e) or under 35 U.S.C 120, 121 or 365(c) is acknowledged.
Accordingly, the effective priority date of the instant application is granted as 4/13/2023.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 3/30/2026 was received. The submission was in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement was considered by the examiner.
Withdrawn Rejections
The 35 U.S.C. 103 rejection of claims 21 and 24-32 has been withdrawn and applied in modified form to address applicants claim amendments to independent claim 21 which describes the replication defective herpes simplex virus which delivers the polynucleotide encoding the bNGF polypeptide to one or more cells of the eye of a subject.
Claim Objections
Claims 7 and 21 are objected to because of the following informalities: the claims contain the acronym bNGF. While acronyms are permissible shorthand in the claims, the first use should include the full recitation followed by the acronym in parentheses. Although bNGF is correctly described in claim 1 as “beta-nerve growth factor (bNGF)”, it is noted that claim 1 is withdrawn without traverse. Appropriate correction is required.
Claim Interpretation
Claim 10 describes a HSV vector “suitable” for delivery into one or more target cells. Under the broadest reasonable interpretation, the claim language does not necessarily require that the HSV vector delivers the bNGF polypeptide only that it is suitable for such an application.
Claims 11, 21, 24 list out target cell types from a subject with a corneal injury. It is noted that at least the corneal epithelial cell would be in contact with the HSV vector upon topical administration.
Claim 21 describes the subject having a corneal would or injury. The broadest reasonable interpretation of corneal injury reads on any injury to the corneal epithelium, Bowman’s layer, corneal endothelium or any innervated corneal nerves.
Maintained 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 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.
Claims 7, 10-11, 15-20 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Krishnan et al. US 2021/0189427, published 6/24/2021 (hereinafter Krishnan, reference of record) in view of Wen et al. US 2022/0339251, published 10/27/2022 (hereinafter Wen, reference of record) and Ferrari et al. "Safety and pharmacokinetics of escalating doses of human recombinant nerve growth factor eye drops in a double-masked, randomized clinical trial." BioDrugs 28 (2014): 275-283 (hereinafter Ferrari, reference of record). This rejection is maintained with respect to claims 7, 10-11 and 15-20 and newly applied to claim 33. A reply to applicants’ traversal is found below.
Claim 7: Krishnan describes a method for delivering therapeutic recombinant nucleic acids using replication defective recombinant herpes simplex viruses (Krishnan, para 7-9). Krishnan describes the use of a pharmaceutically acceptable carrier or excipient for topical administration (Krishnan, para 14, 206). Krishnan also describes subretinal administration routes, which indicates that the aforementioned method is applied to an eye condition or disease for therapeutic relief (Krishnan, para 14, 206-207). Krishnan provides preferred embodiments to therapeutic recombinant nucleic acids including bone morphogenic protein receptor type-2 polypeptide (BMPR2) among others (Krishnan, para 11, 25, 70, 123 and claim 118). However, Krishnan does not describe the delivery of a polynucleotide encoding a beta nerve growth factor (bNGF) or an express description of administering the pharmaceutical composition topically to the eye as a method of treating neurotrophic keratitis.
Claim 10: Krishnan describes generating replication defective recombinant herpes simplex viruses which for delivering therapeutic transgenes like BMPR2 and would therefore be “suitable” for delivering polynucleotides encoding the bNGF polypeptide to one or more target cells of a subject’s eye (Krishnan, para 11, 25, 70, 123 and claim 118; see claim interpretation above).
Claim 15: Krishnan describes the use of recombinant herpes simplex viruses including HSV-1 and HSV-2 (Krishnan, para 8).
Claims 16-17: Krishnan describes generating replication defective recombinant herpes simplex viruses by targeted inactivating mutations to one or more copies of ICP0, ICP4, ICP22, ICP27, ICP47, thymine kinase, UL41 and UL55 (Krishnan, para 9). Krishnan describes how these inactivating mutations allow for the long-term expression of therapeutic genes without HSV toxicity (Krishnan, para 9, 176).
Claim 19: Krishnan describes human target cells and treating human subjects (Krishnan, para 12 and 18).
Claim 20: Krishnan describes a HSV vector that has reduced cytotoxicity as compared to a corresponding wild-type HSV (Krishnan, para 12).
Claim 33: Krishnan describes administration of the pharmaceutical composition one, two, three four or five times per day to the subject (Krishnan, para 241).
Claims 7 and 11: Wen describes the delivery of beta nerve growth factor (bNGF) using herpes viral vectors (Wen, para 6 and 102). Wen describes ophthalmic formulations, eye ointments and topical solutions (Wen, para 88, 92). Wen describes topical administration such as the use of eye drops (Wen, para 85, 92).
Claims 18: Wen discloses a bNGF polypeptide sequence with 100% sequence similarity to SEQ ID NO: 363 (Sequence search results shown below).
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It would have been prima facie obvious to one of ordinary skill in the art to deliver bNGF as described by Wen in the replication defective recombinant herpes simplex viruses disclosed by Krishnan as a therapeutic eye treatment. It would have been a matter of simple substitution of one known therapeutic polypeptide like BMPR2 disclosed by Krishnan for bNGF as described by Wen to obtain predictable results. One would have been motivated to make this substitution given that Wen states that bNGF would be useful in an ophthalmic formulation for treating optic nerve injuries (Wen, para 92). One would have a reasonable expectation of success given that Wen expressly lists HSV vectors as a possible gene vector to deliver bNGF. Furthermore, replication defective recombinant HSV offer numerous advantages over traditional HSV vectors including longer-term expression of therapeutic genes without HSV toxicity (Krishnan, para 9, 176, 188).
However, either Krishnan nor Wen describes treating neurotrophic keratitis as an eye condition.
Claims 7: Ferrari describes a double-masked randomized clinical trial examining the therapeutic applications of NGF towards treating ocular conditions like neurotrophic keratitis (Ferrari, abstract and discussion para 1). Ferrari found that rhNGF eye drops were well tolerated with no detectable clinical evidence of systemic adverse side effects (Ferrari, abstract). Furthermore, Ferrari describes NGF treatment as a promising therapy for a variety of ocular conditions involving damage of the cornea (inclusive of the corneal epithelial cell layer), conjunctiva, retina and optical nerve (Ferrari, discussion para 1).
It would have been prima facie obvious to one of ordinary skill in the art to deliver the replication defective HSV vector encoding bNGF as described by Krishnan in view of Wen as a treatment for neurotrophic keratitis as described by Ferrari. It would have been a matter of combining prior art elements according to known methods to yield predictable results. One would have been motivated to make this combination given that Ferrari demonstrated that bNGF is an effective treatment for ocular conditions like neurotrophic keratitis using rhNGF eye drops (Ferrari, abstract and discussion para 1). Thus, one of ordinary skill would be motivated to express NGF as a HSV based gene therapy rather than directly administering the protein as a treatment for neurotrophic keratitis given that a longer-term or permanent effect may be achieved while reducing the necessity for repeat administration and potential negative immune responses. One would have a reasonable expectation of success given that the replication defective recombinant HSV vectors described by Krishnan offer longer-term expression of therapeutic genes without HSV toxicity (Krishnan, para 9, 176, 188). Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered claims 7, 10-11, 15-20 and 33 to have been prima facie obvious to at the time the invention was made.
Response to Traversal
Applicant traverses the rejection by arguing that one of ordinary skill in the art would have no motivation to modify the teachings of Krishnan to arrive at the claimed invention with a reasonable expectation of success. Applicant traverses the rejection by arguing that one of skill in the art would be motivated to avoid using an HSV vector as a delivery vehicle to express bNGF in the eye to treat neurotrophic keratitis because the most common cause of the impairment of corneal sensations are herpetic keratitis that damage the trigeminal ophthalmic branch and references Sacchetti, Bonini and Chucair-Elliott for support. Applicant submits that therefore one of skill in the art would not me motivated to start with any type of HSV vector for the treatment of neurotrophic keratitis. Applicant argues that reasonable expectation of success should be supported by evidence and impermissible hindsight must be avoided.
These arguments have been fully considered, but were not found persuasive since Krishnan does not describe the use of a HSV-1 vector but a replication defective HSV-1 vector by targeted inactivating mutations to one or more copies of ICP0, ICP4, ICP22, ICP27, ICP47, thymine kinase, UL41 and UL55 (Krishnan, para 9). Krishnan describes how these inactivating mutations allow for the long-term expression of therapeutic genes without HSV toxicity (Krishnan, para 9, 176). It appears applicant is arguing that the prior art (Sacchetti, Bonini and Chucair-Elliott) teach away from the claimed solution. Teaching away requires the prior art to criticize, discredit, or otherwise discourage the claimed solution, see MPEP § 2141.02(VI): “the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed.” Since the prior art clearly does not do this, this argument is unconvincing.
Applicant points to the declaration submitted on 3/30/2026 by Dr. Weldon Haw which argues that HSV infection of the eye is a major cause of neurotrophic keratitis and therefore one of ordinary skill would be deterred from using such a vector for delivering bNGF. Furthermore, the declaration points to Fig 1 of Exhibit A which shows a comparison of total human NGF post-single HSV-bNGF or six-time rh-NGF topical administration to wound corneas. Applicant argues that these secondary considerations and unexpected results make the amended claims not obvious over Krishnan in view of Wen and Ferrari.
These arguments have been fully considered, but were not found persuasive since Exhibit A shows comparative data between total human NGF in wild-type mouse eyes post single HSV-bNGF or six time-rhNGF topical administration to wounded corneas. However, objective evidence of non-obviousness must be commensurate in scope with the claims which the evidence is offered to support, see MPEP 716.02(d). What is unclear is now the replicative deficient HSV-bNGF would compare to the replicative competent HSV-bNGF described by Wen. The instant rejection argues that it would have been prima facie obvious to one of ordinary skill in the art to deliver bNGF as described by Wen in the replication defective recombinant herpes simplex viruses disclosed by Krishnan as a therapeutic eye treatment. It would have been a matter of simple substitution of one known therapeutic polypeptide like BMPR2 disclosed by Krishnan for bNGF as described by Wen to obtain predictable results. Since the declaration and arguments do not address this relevant comparison, the rejection is maintained accordingly.
Claims 21, 24-30 and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Krishnan et al. US 2021/0189427, published 6/24/2021 (hereinafter Krishnan, reference of record) in view of Wen et al. US 2022/0339251, published 10/27/2022 (hereinafter Wen, reference of record) as evidenced by DelMonte et al. "Anatomy and physiology of the cornea." Journal of Cataract & Refractive Surgery 37.3 (2011): 588-598 (hereinafter DelMonte, reference of record). This rejection is newly applied to address applicants claim amendments on 3/30/2026.
Claim 21: Krishnan describes a method for delivering and expressing therapeutic recombinant nucleic acids using replication defective recombinant herpes simplex viruses (Krishnan, para 7-9). Krishnan describes the use of a pharmaceutically acceptable carrier or excipient for topical administration (Krishnan, para 14, 206). Krishnan also describes subretinal administration routes, which indicates that the aforementioned method is applied to an eye condition or disease for therapeutic relief (Krishnan, para 14, 206-207). Krishnan provides preferred embodiments to therapeutic recombinant nucleic acids including bone morphogenic protein receptor type-2 polypeptide (BMPR2) among others (Krishnan, para 11, 25, 70, 123 and claim 118). However, Krishnan does not describe the delivery of a polynucleotide encoding a beta nerve growth factor (bNGF) or an express description of administering the pharmaceutical composition topically to the eye of a subject with a corneal injury.
Claim 25: Krishnan describes the use of recombinant herpes simplex viruses including HSV-1 and HSV-2 (Krishnan, para 8).
Claims 26-27: Krishnan describes generating replication defective recombinant herpes simplex viruses by targeted inactivating mutations to one or more copies of ICP0, ICP4, ICP22, ICP27, ICP47, thymine kinase, UL41 and UL55 (Krishnan, para 9). Krishnan describes how these inactivating mutations allow for the long-term expression of therapeutic genes without HSV toxicity (Krishnan, para 9, 176).
Claim 29: Krishnan describes human target cells and treating human subjects (Krishnan, para 12 and 18).
Claim 30: Krishnan describes a HSV vector that has reduced cytotoxicity as compared to a corresponding wild-type HSV (Krishnan, para 12).
Claim 34: Krishnan describes administration of the pharmaceutical composition one, two, three four or five times per day to the subject (Krishnan, para 241).
Claims 21 and 24: Wen describes the delivery of beta nerve growth factor (bNGF) using herpes viral vectors (Wen, para 6 and 102). Wen describes ophthalmic formulations, eye ointments and topical solutions (Wen, para 88, 92). Wen describes topical administration such as the use of eye drops (Wen, para 85, 92). As stated in the claim interpretation section, the broadest reasonable interpretation of corneal injury reads on any injury to the corneal epithelium, Bowman’s layer, corneal endothelium or any innervated corneal nerves. Thus, Wen’s description of treating optic nerve injuries via topical administration reads on treating a corneal injury and the cells listed in claim 24 (Wen, para 3, 85). This interpretation is supported by the disclosure of DelMonte wherein a description of the anatomy and physiology of the cornea is provided. DelMonte states that the cornea is one of the most heavily innervated and sensitive tissues in the body (DelMonte, pg 592 col 2). DelMonte shows that the cornea epithelium is the outermost later of the eye and would therefore be in contact with the bNGF vector upon topical administration.
Claim 28: Wen discloses a bNGF polypeptide sequence with 100% sequence similarity to SEQ ID NO: 363 (Sequence search results shown below).
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It would have been prima facie obvious to one of ordinary skill in the art to deliver bNGF as described by Wen in the replication defective recombinant herpes simplex viruses disclosed by Krishnan as a therapeutic eye treatment. It would have been a matter of simple substitution of one known therapeutic polypeptide like BMPR2 disclosed by Krishnan for bNGF as described by Wen to obtain predictable results. One would have been motivated to make this substitution given that Wen states that bNGF would be useful in an ophthalmic formulation for treating optic nerve injuries (Wen, para 92). One would have a reasonable expectation of success given that Wen expressly lists HSV vectors as a possible gene vector to deliver bNGF. Furthermore, replication defective recombinant HSV offer numerous advantages over traditional HSV vectors including longer-term expression of therapeutic genes without HSV toxicity (Krishnan, para 9, 176, 188). Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered claims 21, 24-30 and 34 to have been prima facie obvious to at the time the invention was made.
Nonstatutory Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the "right to exclude" granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Langi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717 .02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP 706.02(1)(1) - 706.02(1)(3) for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 7, 10-11, 15-21, 24-30 and 33-34 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of US Patent No. 11,865,148 published on 1/9/2024 (application number 18/060,515) in view of Wen et al. US 2022/0339251, published 10/27/2022 (hereinafter Wen, reference of record). Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims would anticipate the instant claims if they were available as prior art. This rejection is newly applied to address applicants claim amendments on 3/30/2026.
Claims 7, 10-11, 15-21, 24-30 and 33-34: The patented claims describe a method for delivering a human transgene to an eye of a subject, wherein the subject has an eye disease associated with vision loss (claim 1). The patented claims describe a replicative deficient herpes simplex virus (HSV-1) encoding one or more polynucleotides to treat a disease of the eye associated with vision loss (Claim 1 and 11). The patented claims describe an inactivating mutation in one or both copies of ICP4 HSV-1 (Claim 14). The patented claims describe the HSV-1 having reduced cytotoxicity when compared to its wild-type counterpart (Claim 9). The patented claims do not describe the HSV-1 vector encoding a bNGF polypeptide as described in independent claims 7 and 21.
However, Wen describes the delivery of beta nerve growth factor (bNGF) using herpes viral vectors (Wen, para 6 and 102). Wen describes ophthalmic formulations, eye ointments and solutions (Wen, para 88 and 92). Wen describes applications to the patient’s eye and neurons thereof, which reads on the various neuronal cell types listed (Wen, para 52, 88 and 92). Wen discloses a bNGF polypeptide sequence with 100% sequence similarity to SEQ ID NO: 363 (Sequence search results shown below).
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It would have been prima facie obvious to one of ordinary skill in the art to deliver bNGF as described by Wen in the replication defective recombinant herpes simplex viruses disclosed by the patented claims as a therapeutic eye treatment. It would have been a matter of simple substitution of one known therapeutic polypeptide for another to obtain predictable results. One would have been motivated to make this substitution given that Wen states that bNGF would be useful in an ophthalmic formulation for an eye treatment (Wen, para 92). One would have a reasonable expectation of success given that Wen expressly lists HSV vectors as a possible gene vector to deliver bNGF. Furthermore, replication defective recombinant HSV offer numerous advantages over traditional HSV vectors including lower toxicity to host cells.
Conclusion
No claims allowed.
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Alexander Nicol
Patent Examiner
Art Unit 1634
/ALEXANDER W NICOL/Examiner, Art Unit 1634
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