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 .
Priority
Acknowledgment is made of applicant’s claim for priority based on a foreign application filed as GB1914826.1 on 10/14/2019.
All claims are given the priority date of 10/14/2019.
Application Status
Receipt is acknowledged of amendment, filed 03/23/2026. Claims 28-30, 33-35, 38, 40-45, 47, 48 and 52-55 are currently pending.
Election/Restriction
Applicant’s election of Group II, drawn to claims 42-45, 47 and 48, in the reply filed on 03/23/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 28-30, 33-35, 38, 40, 41, and 52-55 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03/23/2026.
Claims 42-45, 47 and 48 are currently under examination.
Information Disclosure Statement
Receipt of acknowledgment of the information disclosure statements filed on 09/12/2022, 06/30/2022 and 04/08/2022 have been received and all references have been considered.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. 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.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 45 and 47 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 a retinal degenerative condition in a subject in need thereof, comprising administering an effective amount of the composition comprising a vector encoding a fusion protein comprising opsin and arrestin, wherein the vector comprises a nucleic acid encoding an opsin polypeptide and an arrestin polypeptide and a peptide linker; wherein in the fusion protein, the opsin polypeptide and the arrestin polypeptide are operably linked by a peptide linker, preferably wherein the retinal degenerative condition is a retinal dystrophy, a rod dystrophy, a rod-cone dystrophy, a cone-rod dystrophy and/or a cone dystrophy within ON-bipolar and/or OFF-bipolar cells, does not reasonably provide enablement for a method of treating a retinal degenerative condition in a subject in need thereof, comprising administering an effective amount of the composition comprising a vector encoding a fusion protein comprising opsin and arrestin, wherein the vector comprises a nucleic acid encoding an opsin polypeptide and an arrestin polypeptide and a peptide linker; wherein in the fusion protein, the opsin polypeptide and the arrestin polypeptide are operably linked by a peptide linker, preferably wherein the retinal degenerative condition is a retinal dystrophy, a rod dystrophy, a rod-cone dystrophy, a cone-rod dystrophy, a cone dystrophy and a macular dystrophy; other forms of retinal or macular degeneration, an ischaemic condition, uveitis or a condition resulting from loss of photoreceptor ability. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention: The claims are drawn to a method of treating a retinal degenerative condition in a subject in need thereof, comprising administering an effective amount of the composition comprising a vector encoding a fusion protein comprising opsin and arrestin, wherein the vector comprises a nucleic acid encoding an opsin polypeptide and an arrestin polypeptide and a peptide linker; wherein in the fusion protein, the opsin polypeptide and the arrestin polypeptide are operably linked by a peptide linker. The method of treating a retinal degenerative condition wherein the retinal degenerative condition is a retinal dystrophy, a rod dystrophy, a rod-cone dystrophy, a cone-rod dystrophy, a cone dystrophy and a macular dystrophy; other forms of retinal or macular degeneration, an ischaemic condition, uveitis or a condition resulting from loss of photoreceptor ability. The nature of the invention is complex in that the function of the fusion protein for treating any retinal degenerative condition is not specified.
Breadth of the claims: The claims encompass: treating any retinal degenerative condition by administering the vector encoding a fusion protein comprising opsin and arrestin, wherein the vector comprises a nucleic acid encoding an opsin polypeptide and an arrestin polypeptide and a peptide linker; wherein in the fusion protein, the opsin polypeptide and the arrestin polypeptide are operably linked by a peptide linker. The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims.
Guidance of the specification and existence of working examples: The specification broadly defines treating a retinal degenerative condition wherein the retinal degenerative condition is a retinal dystrophy, a rod dystrophy, a rod-cone dystrophy, a cone-rod dystrophy, a cone dystrophy and a macular dystrophy; other forms of retinal or macular degeneration, an ischaemic condition, uveitis or a condition resulting from loss of photoreceptor ability (Page 27, Lines 6-10). However, the specification and/or the working examples does not teach the method steps or evidence or how the fusion protein vector is capable of treating any and all of the retinal degenerative conditions listed within the instant claim and specification.
Working examples 1-3 included a live cell assay of G protein activation to measure kinetics of opsin signaling; specifically, the aim was to improve the temporal resolution of the rod opsin light response under heterologous expression (Pages 60-63). Working examples 4-6 describe experiments including the opsin and arrestin fusion proteins for improved temporal resolution of rod opsin, without affecting response amplitude (Page 63-69). Specifically, the experiements shown in working examples 4-6 concluded that the optimum trade-off between maintaining peak response and reducing response lifetime was obtained by tethering Arr3A to the Rod6A mutant with a 10nm linker (Page 69, Lines 29-31). Working example 7 describes the materials and methods used in working examples 1-6 (Pages 70-75). Working example 8 describes that each experiment used an adeno-associated virus containing one of the following optogenetic transgenes: 1. Rod6A-10nm-Arrestin3A - This is phosphonull human rod opsm mutant fused to a phosphorylation-independent visual arrestin mutant by a semi-flexible linker; 2. Rod opsin El22Q - This is human rod opsin with a non-synonymous point mutation that causes faster decay of meta-II signalling state. The smaller size of this transgene allows us to co-express with a fluorescent mCherry reporter; or 3. Rod opsin WT - This is wildtype human rod opsin, used as a positive control for MEA experiments. This transgene was co-expressed with an mCherry fluorescent reporter (Page 75, [0058]). Working example 8 teaches that the mouse models were retinally degenerate and express Cre recombinase under control of the Grm6 promoter exclusively in the rod ON-bipolar cells (Page 76, Lines 1-5). Working example 8 provides that the Rod6a-10nm-Arr3A has transient excitatory responses to light in retinal degenerate retinas (Page 76, Lines 9-24).
However, none of the working examples provide the steps required within the mouse model for specifically treating any and all of the retinal degenerative conditions. Furthermore, the method outlined in claim 45 only comprising the single step of “treating a retinal degenerative condition” only recites a use and not an active manipulative act of how the treatment of any retinal degenerative condition is capable.
Predictability and state of the art: For some relevant background, Mure et al (Cell Reports, 25, 2497-2509.e4) teaches using rAAV2/2 vectors comprising a fusion protein wherein Opn4 is fused via 2A peptide linker to β-arrestin 1 or β-arrestin 2 into the retinas of adult rd;Opn4-/- mice (Page 2504, Column 1 bridging Column 2). Mure teaches the retinas used specifically exhibited degeneration of rod and cone photoreceptors of the ON-bipolar retinal cells (Page 2498, Column 2).
Kaur et al (Int J Mol Sci. 2021 Dec 30;23(1):386; Pgs. 1-20) teaches that retinal neurodegeneration is predominantly reported as the apoptosis or impaired function of the photoreceptors (Page 1, Abstract). Kaur teaches there is unpredictability and complexity in what triggers retinal diseases, such as genetic and environmental factors, and therefore there is a complexity of how each retinal degenerative condition behave leading to complexity in treatments between retinal dystrophies and macular degeneration (Page 3, Paragraph 1 bridging Page 4, Paragraph 3). Kaur teaches that specifically there are different secondary inflammatory responses within the different retinal degenerative conditions leading to downstream effects; specifically, the impact of inflammatory responses in the case of IRDs is often due to chronic excessive reaction of the cells and cellular products involved, leading to cell degeneration and apoptosis in the retina (Page 6, Paragraph 2).
Amount of experimentation necessary: In order to practice the claimed invention, an immense amount of experimentation would be required. As disclosed above, the specification itself provides description of a fusion protein vector encoding a fusion protein comprising opsin and arrestin, wherein the vector comprises a nucleic acid encoding an opsin polypeptide and an arrestin polypeptide and a peptide linker; wherein in the fusion protein, the opsin polypeptide and the arrestin polypeptide are operably linked by a peptide linker. No description is provided of any successful example of the fusion protein vector treating any and/or all retinal degenerative conditions. Except for the fusion protein vector disclosed and claimed, for experimentation, first, fusion protein vector would need to be tested in order to confirm that it would be capable of successfully capable of being administered to a subject. Finally, the fusion protein vector would need to be tested in an art-accepted model in order to identify if it is successfully capable of treatment and/or prevention of all known retinal degenerative conditions. Therefore, experiment could be conducted, but in view of the specification there does not appear to be any amount of experimentation that would be sufficient to reliably produce the exact method of the invention for the treatment of any retinal degenerative condition within an individual. Such experimentation would not be possible due to not having the steps or structure of the method of use of the claimed fusion protein vector. Therefore, it would require immense amount of unpredictable experimentation to practice the claimed invention with such variants in the possible result.
In view of the breadth of the claims and the lack of guidance provided by the specification as well as the unpredictability of the art, the skilled artisan would have required an undue amount of experimentation to make and/or use the claimed invention. Therefore, claims 45 and 47 are not considered to be fully enabled by the instant disclosure.
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 42, 45 and 47 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.
Claims 42, 45 and 47 are vague and indefinite in that the metes and bounds of the phrase “preferably” are unclear. The phrase is unclear in that it does not provide whether limitations following the phrase is required or optional. It would be remedial to replace the phrase “preferably” with “optionally” or amending the claim to remove the phrase entirely.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 42-45, 47 and 48 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Mure et al (Cell Reports, 25, 2497-2509.e4).
Regarding claims 42 and 43, Mure teaches using rAAV2/2 vectors comprising a fusion protein wherein Opn4 is fused via 2A peptide linker to β-arrestin 1 or β-arrestin 2 into the retinas of adult rd;Opn4-/- mice (Page 2504, Column 1 bridging Column 2). Mure teaches the retinas with Opn4wt-F2A-βarr2 also showed sustained responses when repetitively subjected to 60-s light pulses (Page 2504, Column 2). Mure teaches that β-arrestin 1 and β-arrestin 2 play distinct, sequential roles in regulating the melanopsin photopigment in intrinsically photosensitive retinal ganglion cells (ipRGCs) (Page 2499, Column 1 and Page 2504, Column 2).
Regarding claim 44, Mure teaches using rAAV2/2 vectors comprising a fusion protein wherein Opn4 is fused via 2A peptide linker to β-arrestin 1 or β-arrestin 2 into the retinas of adult rd;Opn4-/- mice (a mouse strain with outer retina degeneration) (Page 2504, Column 1 bridging Column 2 and Page 15(e1); Bacterial and Virus Strains Table). Mure teaches RGCs transduced with Opn4wt-F2A-βarr2 displayed shorter responses, which is consistent with a faster signal termination and Opn4wt-F2A-βarr1 RGCs displayed responses that were similar to Opn4wt alone, but repetition of the same stimulus revealed a decreased adaptation rate when βaRR1 was overexpressed, therefore, retinas transduced with Opn4wt-F2A-βarr2 displayed shorter responses compared to Opn4wt-F2A-βarr1 RGCs and Opn4wt alone (Page 2504, Column 2).
Regarding claims 45 and 47, Mure teaches using rAAV2/2 vectors comprising a fusion protein wherein Opn4 is fused via 2A peptide linker to β-arrestin 1 or β-arrestin 2 into the retinas of adult rd;Opn4-/- mice (a mouse strain with outer retina degeneration) (Page 2504, Column 1 bridging Column 2 and Page 15(e1); Bacterial and Virus Strains Table). Mure teaches expressed melanopsin specifically in the native ipRGCs (intrinsically photosensitive retinal ganglion cells) (Page 2502, Column 1). Mure teaches it discovers that β-arrestin 1 and β-arrestin 2 act sequentially to support this: β-arrestin 2 terminates the signal, while β-arrestin 1 recycles the pigment, thus this dual mechanism is vital for restoring light sensitivity in damaged retinas (Page 2505, Column 1 bridging Column 2). Mure teaches the AAV2 serotype packaged viruses were concentrated and purified in PBS and intravitreally administered (Page 16 (e2); AAV2/2 virus production and intraocular injection).
Regarding claim 48, Mure teaches using rAAV2/2 vectors comprising a fusion protein wherein Opn4 is fused via 2A peptide linker to β-arrestin 1 or β-arrestin 2 into the retinas of adult rd;Opn4-/- mice (a mouse strain with outer retina degeneration) (Page 2504, Column 1 bridging Column 2 and Page 15(e1); Bacterial and Virus Strains Table). Mure teaches RGCs transduced with Opn4wt-F2A-βarr2 displayed shorter responses, which is consistent with a faster signal termination and Opn4wt-F2A-βarr1 RGCs displayed responses that were similar to Opn4wt alone, but repetition of the same stimulus revealed a decreased adaptation rate when βaRR1 was overexpressed, therefore, retinas transduced with Opn4wt-F2A-βarr2 displayed shorter responses compared to Opn4wt-F2A-βarr1 RGCs and Opn4wt alone (Page 2504, Column 2). Mure teaches that retinas with Opn4wt-F2A-βarr2 showed sustained responses when repetitively subjected to 60-s light pulses (Page 2504, Column 2). Therefore, generating a photoactivatable cell.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDRA ROSE LIPPOLIS whose telephone number is (703)756-5450. The examiner can normally be reached Monday-Friday, 8:00am to 5:00pm EST.
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/ALEXANDRA ROSE LIPPOLIS/Examiner, Art Unit 1637
/CELINE X QIAN/Primary Examiner, Art Unit 1637
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