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 the Claims
Claims 1, 5, 8, 9, 17-18, 34-35, 62, 64-66, 72-73, 97, and 101-104 are currently pending.
Claims 1 and 62 are amended.
Claim 97 has been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Invention, there being no allowable generic or linking claim.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 2-4, 6-7, 10-16, 19-33, 36-61, 63, 67-1, 74-96, and 98-100 remain cancelled.
Claims 1, 5, 8, 9, 17-18, 34-35, 62, 64-66, 72-73, 97, and 101-104 have been considered on the merits.
Note to Applicant
Claim 36 was previously indicated as cancelled in the reply filled on 04/30/2025 and has not been properly reinstated under 37 CFR 1.121. The claim set filled on 10/20/2025 indicates claim 36 as “Previously Presented”, however claim 36 remains cancelled, and the listing of its text in the claim listing filled 10/20/2025 is improper. Correction of the claim status is required.
Withdrawn Rejections
The objection made onto claim 62 is withdrawn light of the arguments submitted on 10/20/2025.
New and Maintained Rejections Necessitated by Amendment
Claim Objections
Claim 1 and 62 are objected to because of the following informalities: a period needs to be included at the end of the claim. Appropriate correction is required.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 34 and 35 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 1 limits the method to a method of “treating rod-mediated vision loss” and claim 34 requires the limitation “wherein the subject has a condition associated with vision loss or impairment due to photoreceptor loss”. The recitation of “rod-mediated” in claim 1 limits the claims to vision loss or impairment due to loss or ailment of rod cells which are a subset of photoreceptor cells. Claim 34 provides wherein the vision loss or impairment is due to any photoreceptor loss which is broader than the “rod-mediated vision loss” of claim 1. Additionally, claim 35 limits “wherein the condition is selected from age-related macular degeneration (AMD), diabetic retinopathy, retrolental fibroplasia, Stargardt disease, retinitis pigmentosa (RP), uveitis, Bardet-Biedl syndrome and eye cancers”. Of these listed ailments to the eye, retrolental fibroplasia, Stargardt disease, and uveitis, do not appear to primarily affect the rod photoreceptors and therefore do not further limit claim 1. Additionally, “eye cancers” encompasses cancers that are rod-mediated and cancers which are not rod-mediated, therefore due to the breadth of “eye cancers”, the limitation also does not further limit claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Claims 1, 5, 8, 9, 17-18, 34-35, 62, 64-66, 72-73, 97, and 101-104 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
A method of treating rod-mediated vision loss or impairment in a subject, comprising:
(a) administering to the subject a therapeutically effective amount of a first AAV-shH10 vector comprising a nucleic acid encoding beta-catenin; and
(b) at least one week after the administering of step (a), administering to the subject a therapeutically effective amount of a second AAV-ShH10 vector comprising a nucleic acid encoding Otx2, a third AAV-ShH10 vector comprising a nucleic acid encoding Crx, and a fourth AAV-ShH10 vector comprising a nucleic acid encoding Nrl.
The specification does not reasonably provide enablement for the method of treating rod-mediated vision loss employing any MG proliferation agent, as recited in line 4 of claim 1. 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.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' " (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
(1) The nature of the invention:
The specification describes the invention as a method of inducing differentiation of Muller glial cells into rod photoreceptors. Also provided are methods of treating vision loss or impairment due to photoreceptor loss.
(2) the breadth of the claims:
The claims broadly encompass a method of treating rod-mediated vision loss in a human subject, comprising the steps of (a) administering a therapeutic amount of Muller glial (MG) cell proliferation agent and (b) administering a therapeutically effective amount of MG cell differentiation agent. Thus, the claims taken together with the specification imply that any MG proliferation agent is capable of being used in the instant method of treating rod-mediated vision loss.
(3) The state of the prior art:
The prior art demonstrates emerging therapies for vision loss including involving the transplantation of retinal pigmented epithelium or other neural progenitors. The prior art demonstrates the benefit of cellular reprogramming of Muller Glial cells in fish and amphibians, however does not appear to demonstrate that benefit in mammalian cells to treat any rod-mediated vision loss or impairment in a subject.
(4) the predictability or unpredictability of the art:
The claims have been amended to embody a method of treating rod-mediated vision loss through the administration of any MG proliferation agent to a subject experiencing vision loss, which is unpredictable.
This method is found to be unpredictable with regards to treating rod-mediated vision loss through the administration of any MG cell proliferation agent. More specifically, the method of treatment is unpredictable in its ability to treat rod-mediated vision loss employing any MG cell proliferation agent.
The specification provides support for the treatment of rat or mouse vision loss models by the provided methods in examples 1-5. Two models are employed in the specification, an NMDA mouse/rat model (Examples 1-2), which models retinal ganglion cell (RGC) depletion, and a Gnat1 -/-: Gnat2cpfl3 mouse model (Examples 3-5), which models rod-deficient congenital night blindness (See Thomas, Reference of record, Table 1).
Applicant has limited the scope of the instant claims to require that the method treats “rod-mediated” vision loss (See claims submitted on 10/20/2025). The only model presented in the specification which is an art recognized model of rod-mediated vision loss appears to be the Gnat -/-: Gnat2cpfl3 mouse model, employed in Examples 3-5. Therefore, the examples which employ the NMDA model of RGC depletion are not representative of a “rod-mediated” vision loss and are not capable of supporting the enablement of the method of treating “rod-mediated” vision loss. Therefore, the analysis of the enabled species of MG cell proliferation agents is limited to those MG cell proliferation agents that are tested on the art recognized rod-mediated vision loss Gnat -/-: Gnat2cpfl3 mouse model.
The specification does not provide support for a method of treating rod-mediated vision loss employing any MG proliferation agent, besides beta-catenin, which are explicitly demonstrated in examples 3-5.
Examples 3 and 4 of the specification provide guidance on performing the method of treating rod-mediated vision loss on the Gnat -/-: Gnat2cpfl3 mouse model employing a nucleic acid encoding beta-catenin as the MG cell proliferation agent. It appears that no other MG proliferation agents are tested specifically using the Gnat -/-: Gnat2cpfl3 mouse model.
Example 5 states that it examines the gene transfer of Ascl1 into the retina, however the methods of the example do not detail the production of an AAV encoding Ascl1, rather beta-catenin is the only recited MG proliferation agent. The opening paragraph of Example 5 states “To examine whether Ascl1 expression leads to MG proliferation, EdU incorporation was analyzed following ShH10-GFAP-mediated gene transfer of wild-type Ascl1 in adult mouse retina at 4 weeks of age and MG cell proliferation was performed as described in Example 1” (pg. 130, para 2). The methods of Example 5 do not mention Ascl1 beyond pg. 130, paragraph 2, but the methods do recite the last paragraph of pg. 130 which defines AAV production and intravitreal injection of “cDNAs encoding GFP, tdTomato, B-catenin, Otx2, Crx and Nrl”. Additionally, Example 5 states “A total of 12 animals were studied, six treated animals, four controls (i.e., beta-catenin delivery omitted from first virus injection)” (pg. 134, para 2). The methods recited in Example 5 do not appear to be identical or accidentally duplicated from any of the other Examples. Therefore, if one were to follow the methods of Example 5, they would not be directed to use Ascl1 as the MG proliferation agent, rather they would be directed to incorporate B-catenin in the method.
Therefore, the specification supports that the only predictable MG proliferation agent employed in the instant method appears to be B-catenin.
The unpredictability of employing the MG proliferation agents Lin28a, Lin28b, Notch, and Ascl1 in the instant method is further supported by Elsaeidi et al (Journal of Neuroscience, 2018).
Elsaeidi teaches about the agents Notch, Ascl1, and Lin28 in the proliferation of MG cells in fish and in mouse retina (abstract). Elsaeidi teaches that “forced expression of Ascl1 or Lin28 can stimulate some MG proliferation in the injured and uninjured mouse retina, respectively; however, most of these cells do not survive” (pg. 2247, col. 1, para 3). Additionally, Ellsaeidi teaches that expression of Ascl1 or Lin28 alone only stimulate a very small amount of MG proliferation, whereas expressing Ascl1 and Lin28 combined is able to stimulate more than 10 fold higher amount of MG proliferation in injured retina. This demonstrates that MG proliferation within the mammalian retina is a complex and highly variable treatment process which requires explicit guidance from the instant specification on how to successfully practice the instant method. Additionally, Elsaeidi teaches about Notch inhibition as it relates to both mammalian and fish retinas. Elsaeidi demonstrates that Notch inhibition, combined with Ascl1 and Lin28a expression, causes widespread MG proliferation in fish retinas (pg. 2258, Col. 2, last para). However, in the mouse retina when Ascl1 and Lin28a are expressed in the presence of a Notch inhibitor the results show no effect on uninjured cells and a suppression of MG proliferation in injured retinas (pg. 2258. Col 1, para 3). Elsaeidi is demonstrating again that MG proliferation in the mammalian retina is complex and not fully understood by showing that methods which enhance fish MG proliferation can be actively negative to MG proliferation in mammalian retina, which renders the method unpredictable.
Therefore, without explicit support from the instant disclosure on how one may practice the method of treatment using any MG proliferation agent, the only predictable MG proliferation agent for the method of treatment of rod-mediated vision loss is b-catenin.
(4) The relative skill of those in the art:
The relative skill of those in the art is high.
(5) The amount of direction or guidance presented and (6) the presence or absence of working examples:
The specification details examples 1-5. Example 1 details Wnt regulation of proliferation of MG cells through a Lin28/Let-7 miRNA-dependent pathway in an NMDA mouse model. Example 2 details the gene transfer of b-catenin to activate MG proliferation without retinal injury in NMDA mouse model. Example 3 details the regeneration of rod photoreceptors from MG cells in adult Gnat -/-: Gnat2cpfl3 mouse retinas by first providing b-catenin as the MG proliferation agent and subsequently providing three vectors, each comprising one of Otx2, Crx, and Nrl to the retina. Example 4 details the restoration of vision after ne novo genesis of rod photoreceptors in Gnat -/-: Gnat2cpfl3 mouse retinas employing b-catenin as the MG proliferation agent and subsequently providing three vectors, each comprising one of Otx2, Crx, and Nrl to the retina. Example 5 describes the gene transfer of Ascl1 to stimulate MG proliferation in adult Gnat -/-: Gnat2cpfl3 , however appears to employ b-catenin in the methods and not Ascl1. Therefore, the specification’s only working examples are those which are optimized for use in NMDA and Gnat -/-: Gnat2cpfl3 mice model retinas.
(7) The quantity of experimentation necessary:
Considering the state of the art as discussed above and the high unpredictability and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to use the claimed invention within the broad scope as instantly claimed.
It is the examiner’s position that one skilled in the art could not practice the invention commensurate in the breadth of the claims without undue experimentation. Therefore, claim 1 and its dependents are rejected under 35 U.S.C. 112, first paragraph, for a lack of scope of enablement.
Response to Arguments
Applicant’s arguments, see Remarks, filed 10/20/2025, with respect to the rejection(s) of claim(s) 1, 5, 8, 9, 17-18, 34-35, 62, 64-66, 72-73, and 101-104 under 35 U.S.C. 112(a) have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection necessitated by Applicant’s amendment is made under 35 U.S.C. 112(a).
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CONSTANTINA E STAVROU whose telephone number is (571)272-9899. The examiner can normally be reached M-F 8:00-5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached on 571-272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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CONSTANTINA E. STAVROU
Examiner
Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632