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 Claims
Claims 22, 23, 26, 28 and 30-47 are pending and under examination. Claims 1-21, 24-25, and 27 are cancelled. Claims 30-47 are new.
Drawings
Applicant’s replacement drawings are received, however, they still do not comply with 37 CFR 1.121(d). New corrected drawings in compliance with 37 CFR 1.121(d) are required in this application because the drawings are of poor quality. It is also noted that the drawings have several informalities such as Figures 13D-13F, 15B, 16B is a graph with no axis labels. Figure 12 is entirely unclear. Applicant is advised to employ the services of a competent patent draftsperson outside the Office, as the U.S. Patent and Trademark Office no longer prepares new drawings. The corrected drawings are required in reply to the Office action to avoid abandonment of the application. The requirement for corrected drawings will not be held in abeyance.
Claim interpretation
A “wild type opsin 5(OpnS) isolated from an animal, or its orthologs, or a fragment or variant thereof” reads on any wildtype opsin 5 from any animal.
MAINTAINED REJECTIONS
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 22-23, 26, 28 and 30-47 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 claim(s) contains 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.
The rejection as it applied to claims 1, 3-4, 6-16, 18, 20 is withdrawn as they are cancelled.
Regarding claim 22: Claim 22 encompasses all opsin5 across all animals, that are coupled to Gq signaling and are sensitive to light, any fragments, or variants, all homologs, paralogs, orthologs that have at least 90% identity to avian, reptile or fish Opn5. Thus the claims encompass a broad genus defined not merely by sequence identity but by function of restoring the retinal-cell light sensitivity through activation of Gq signaling.
Example 1 of the specification demonstrated that opsin 5 in chicken, and turtle exhibit light induced Gq mediated calcium signaling, whereas, mice and human opn5 do not exhibit light-induced calcium response under tested conditions. (See Example 1). The specification stated that these Opn5 orthologs are 80-90% identical by their protein sequence, thus the specification itself demonstrates that sequence similarity itself alone is not indicative of functional activity, rather, the demonstrated activity is species dependent.
The specification further stated that in Example 4, that whole genes corresponding to numerous Opn5 orthologs from vertebrates were synthesized, expressed in HEK293T cells and subjected to calcium imaging in the presence and absence of 470nm blue light. However, the disclosure that various orthologs does not without results establish possession of every claimed avian, reptile or fish Opn5 ortholog having the claimed Gq mediated retinal light sensitivity restoring activity. In particular, the specification does not establish that each member of the claimed genus or a representation of the genus possesses the claimed functional property.
The specification provides functional evidence for cOPN5 and tOPN5 and Applicant has additionally identified functional data for OPN5 from the great white shark. These disclosures provide evidence for particular species within the avian, reptile and fish groups. However, the claimed genus extends beyond those particular species to encompass Opn5 orthologs throughout the respective animal classes as well as fragments and variants satisfying the claimed sequence-identity and functional limitations. The specification does not provide sufficient representative species or structural/functional information demonstrating possession of the entire claimed genus, particularly in view of the specification’s own demonstration of unpredictability among species.
Response to Applicant Arguments:
Applicants argued that the amendment sufficiently narrows the claim. However, it is asserted that the claimed genus is extremely broad because it combines three entire animal classes with multiple sequence identity thresholds, orthologs , fragments and variants while additionally requiring functional limitation (Gq signaling). It is also noted that orthologs generally retain the same function. However, as described above, applicant’s own specification undermines the proposition as applied to this claimed genus. The specification establishes that orthology and substantial sequence identity does not necessarily establish claimed light sensitive Gq activity. Applicant relied on the 90.04% sequence-consensus analysis and argued that this supports the claimed > or = 90% sequence-identity limitation as a reasonable generalization. Even assuming the sequence identity requirement is satisfied, it is submitted that the sequence identity does not establish the claimed functional property. The claim requires both the specified sequence relationship and the functional ability of restoring the retinal light-sensitivity through Gq signaling. The specification does not demonstrate that the functional property tracks the claimed sequence identity threshold across the claimed genus. It is reiterated that the specification describes testing numerous Opn5 orthologs, but the disclosed testing does not establish possession of the entire claimed functional genus.
Claims 22-23, 26, 28 and 30-47 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 enablement requirement.
The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claims 22-23, 26, 28 and 30-37 require a method of treating a condition involving loss of sensitivity to light in retina. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. While enabling for specific embodiments such as administration of cOpn5 to retinal ganglion in a subject having retinal degeneration wherein the opn5 is activated by blue light to restore light responsiveness, the full scope of the claimed invention is not enabled.
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). 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, a (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 these factors are considered, a sufficient number are discussed below so as to create a prima facie case.
The claims are drawn to a method of treating a condition involving loss of sensitivity to light in retina. The claim language is broad enough to encompass conditions involving loss of retinal-cell light sensitivity associated with diseases having materially different underlying pathologies. As an example, Glaucoma is characterized by progressive degeneration of retinal ganglion cells and changes in optic nerve. The disclosed strategy, however, depends upon expression of Opn5 in RGCs to provide alternative light-responsive signaling pathway. The specification does not support or provide a glaucoma model as an example or other evidence establishing that the claimed method restores useful visual function in the setting of progressive RGC loss. (See Weinreb Abstract; See PTO-892 of 06/03/2026). As another example, optic neuritis involves inflammation of the optic nerve. (See Bennet Abstract; See PTO-892 of 06/03/2026). The specification provides no working examples of optic neuritis model or any other optic nerve disorder using an opn5-mediated Gq signaling in retinal cells. (See Jones, first para, See PTO-892 of 06/03/2026). As such the claims potentially cover retinal detachment, macular degeneration, or other visual or retinal dysfunction. The working examples therefore establish a particular therapeutic application rather than the full scope of the claimed genus. The MNU model represents chemically induced retinal degeneration and the rd1/rd1 model represents inherited retinal degeneration. Both models demonstrate restoration of light responsiveness following chicken opn5 expression in RGCs. It is submitted that the working examples therefore establish a particular therapeutic application rather than the full scope of the claimed genus.
Regarding claim 39: It is also pointed out that the specification provides no evidence or technical guidance establishing that the disclosed opn5/Gq mechanism will produce the claimed therapeutic result when applied to the substantially different cell types such as a photoreceptor cell, a retinal rod cell, a retinal cone cell, a retinal ganglion cell, a bipolar cell, a ganglion cell, a horizontal cell, a multipolar neuron, a Muller cell or an Amacrine cell. It is further noted that before the relevant filing date, it was known in the art to express light-sensitive proteins in surviving retinal neurons to impart photosensitivity to a degenerated retina after loss of photoreceptors. For example, Pan established proof of concept studies and restoration of light responses and visually guided behavior in animal models including by targeting retinal ganglion cells. (See Pan et al; PTO-892). However the prior art does not establish that any particular opn5 ortholog, fragment or variant satisfying a sequence identity threshold with necessarily possess the claimed light-0sensitive Gq activity or will necessarily restore visual function when expressed in each of the diverse retinal cell types and disease contexts encompassed by the claims. While lack of a working embodiment cannot be a sole factor in determining enablement, the absence of substantial evidence, in light of the unpredictable nature of the art and the direction applicants present, provides additional weight to the lack of enablement in consideration of the Wands factors as a whole. Thus, one of ordinary skill in the art would not have a reasonable expectation of successfully treating any other disease than retinal cell degeneration by performing the claimed method.
WITHDRAWN REJECTIONS
Claims 4, 7-11, 12, 15, 16 and 22-23 were rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as failing to set forth 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.
The rejection of claims 4, 7-11, 12, 15, 16 is withdrawn following cancellation. The rejection of claims 22-23 is withdrawn following cancellation of preferable embodiments.
Claim Rejections - 35 USC § 101
Claims 1, 3-4, 6-14 and 20 were rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more.
The rejection is withdrawn following cancellation of the claims
Claim Rejections - 35 USC § 102
Claims 1, 3, 6-7, 13-16, 18, 20, 22-23, 26 and 28 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lucas et al (EP3578197A1; Published Dec 11, 2019; hereinafter "Lucas;" See PTO-892) as evidenced by Dai et al (Sci China Life Sci. 2022 Jul; hereinafter “Dai;” See IDS 05/10/2024).
Claims 1, 4, 8 and 12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yamashita et al (Proc Natl Acad Sci U S A. 2010 Dec 21; hereinafter "Yamashita;" See IDS 05/10/2024) as evidenced by Dai et al (Sci China Life Sci. 2022 Jul; hereinafter “Dai;” See IDS 05/10/2024).
Claim 1, 4 and 10 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tomonari et al (Dev Dyn. 2008 Jul; hereinafter "Tomonari;" See IDS 05/10/2024) as evidenced by Dai et al (Sci China Life Sci. 2022 Jul; hereinafter “Dai;” See IDS 05/10/2024).
The rejections are withdrawn following cancellation of the claims 1-21. New rejections of claims 22-23 are set forth below.
Double Patenting
Claims 1, 3-4, 6-16, 18, 20, 22, 23, 26, and 28 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-15, 17,19, 21-22, and 25 of copending Application No. 18/709,383 (reference application).
The rejection is withdrawn following filing of terminal disclaimer.
NEW REJECTIONS AS NECESSITATED BY CLAIM AMENDMENTS
Claim Rejections - 35 USC § 112
Claims 22-23, 26, 28 and 30-47 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 enablement requirement.
Claims 22-23, 26, 28 and 30-47 encompass methods of treating a disease or condition involving loss of sensitivity to light of a retinal cell by administering a light-sensitive Opn5. While enabling for specific embodiments such as administration of cOpn5 to retinal ganglion in a subject having retinal degeneration wherein the opn5 is activated by blue light to restore light responsiveness, the full scope of the claimed invention is not enabled.
As indicated above, the claims are not limited to a particular disease, condition, etiology, retinal-cell type, or retinal pathology. Further, the claimed light-sensitive Opn5 encompasses wild-type Opn5 from an avian, reptile, or fish animal, as well as qualifying orthologs, fragments, and variants having the recited sequence identity and the claimed activity of restoring retinal-cell light sensitivity through activation of Gq signaling. Accordingly, the scope of the claims encompasses a broad genus of proteins and a broad genus of diseases and conditions to which those proteins are purportedly applicable.
The factors to be considered in determining whether undue experimentation is required are summarized in In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir. 1988). The Wands factors include: (1) the quantity of experimentation necessary, (2) the amount or direction of 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 no single factor is dispositive, the factors considered as a whole establish a prima facie case of lack of enablement.
The breadth of the claims is significant. With respect to the claimed Opn5, the claims encompass proteins extending across avian, reptilian, and fish species and further encompass orthologs, fragments, and variants satisfying the recited sequence-identity and functional requirements. The specification, however, provides only limited functional guidance for determining which members of this broad genus will successfully provide the claimed Gq-mediated light response. Example 1 demonstrates that chicken Opn5 and turtle Opn5 exhibit strong light-induced calcium signaling, whereas human and mouse Opn5 do not exhibit a light-induced calcium response under the tested conditions. The specification states that the tested Opn5 proteins share approximately 80-90% protein sequence identity. Thus, the specification itself demonstrates that substantial sequence similarity and orthology do not necessarily predict the relevant functional activity.
Example 4 states that numerous vertebrate Opn5 orthologs were synthesized, expressed, and tested for light-induced calcium signaling. However, the disclosure of testing numerous orthologs does not establish that the full genus encompassed by the claims is enabled. In particular, the specification does not provide sufficient results or guidance establishing a reliable sequence-function relationship that would permit one of ordinary skill in the art to identify, without undue experimentation, which of the numerous claimed orthologs, fragments, and variants will possess the claimed activity. As such the issue at hand is not merely the number of sequences that could theoretically fall within the claims, but the absence of sufficient guidance for determining which members of the claimed genus will function as required by the claims.
Applicant's reliance on a 90.04% consensus among selected avian Opn5 sequences likewise does not establish enablement of the full claimed genus. A consensus value does not itself establish the functional activity of each individual sequence, and the specification does not establish that the claimed Gq-mediated activity necessarily follows from satisfying the claimed sequence-identity threshold. Indeed, the specification's comparison of functional and nonfunctional Opn5 orthologs demonstrates the uncertainty of predicting the relevant activity based solely upon sequence similarity. Further the specification gives no direction regarding what fragments or variants meet the required sequence identity threshold and meet the functional requirement of Gq signaling. It is noted that regarding the state of art , while the skilled artisan knew how to generate opn5 fragments, or variants, the prior art did not provide a general rule permitting the skilled artisan to predict an arbitrary opn5 ortholog, fragment or variant having at least 90% sequence identity would retain the claimed functional Gq-mediated activity. Accordingly, the state of the art would have provided one of ordinary skill in the art with techniques for constructing and testing particular opsin variants and with a general understanding that modification of an opsin sequence could alter its functional properties. However, the prior art did not establish a general correlation by which one of ordinary skill in the art could predict that an arbitrary Opn5 ortholog, fragment, or variant having at least 90% sequence identity to a wild-type Opn5 would necessarily retain the claimed light-sensitive Gq activity.
As such the claims encompass a broad genus of Opn5 orthologs, fragments, and variants defined in part by sequence identity and in part by the functional requirement of restoring retinal-cell light sensitivity through activation of Gq signaling. The specification does not provide sufficient guidance for identifying, from sequence identity alone, which members of this genus will possess the claimed activity. Thus, although the state of the prior art provided techniques for generating and screening individual opsin variants, the prior art did not make the functional properties of the full claimed genus predictable. As such, the skilled artisan would therefore be required to perform substantial screening and experimentation to determine which of the claimed Opn5 variants and fragments possess the required activity.
Claim Rejections - 35 USC § 103
Claims 22-23, 26, 28, 30, 35-36, 38-42, 44-47 are rejected under 35 U.S.C. 103 as being unpatentable over Lucas et al (EP3578197A1; Published Dec 11, 2019; hereinafter "Lucas;" See PTO-892) as evidenced by Dai et al (Sci China Life Sci. 2022 Jul; hereinafter “Dai;” See IDS 05/10/2024).
Regarding claim 22-23, 30, 38-42, 44-45, 47: Lucas taught a method of treating a retinal degenerative disease using a nucleic acid vector comprising a nucleic acid sequence encoding a human photoreceptor protein. (See Lucas claim 9). [0033] of the specification of Lucas indicated that the nucleic acid sequence for use in the present invention may be selected from the group consisting of rhodopsin, melanopsin, a cone opsin (in particular LWS opsin, MW opsin, and SWS opsin), neuropsin (Opn5), encaphalopsin (Opn3), a parapineal opsin, VAopsin, parapinopsin; parietopsin, pinopsin, TMT opsin, Jelly fish opsin, C-opsin, cryptochrome, and any invertebrate retinal opsins and/or opsins normally supporting extra-retinal photosensitivity in animals. The neuropsin disclosed/taught by Lucas reads on the claimed “wild type opsin 5(OpnS) isolated from an animal, or its orthologs, or a fragment or variant thereof having the activity of restoring sensitivity to light of the retinal cell through activating Gq signaling and having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of the wild type opsin 5(OpnS), and wherein the animal is an avian, a reptile, or a fish.” With respect to the limitation of restoring “sensitivity to light of the retinal cell through activating Gq signaling,” Dai is cited as evidence of cOpn5 property of “blue light-triggered, Gq-dependent Ca2+ release from intracellular stores and protein kinase C activation.” Dai indicated that “[s]trong Ca2+ transients were evoked by brief light pulses of merely 10 ms duration and at 3 orders lower light intensity of that for common optogenetic tools.“ (See Dai Abstract). It is submitted that a brand-new use of an old molecule may be patentable, where the particular use would not have been obvious to one of ordinary skill in the art. Here, Lucas already taught the use of Opn5 in a method of treating a retinal degenerative disease. As pointed out in the Claim Interpretation section, the current claims encompass Opn5 from any species. Further, Dai showed chicken Opn5 as supporting extra-retinal photosensitivity in animal cells. (See Dai Abstract). As such it would have been obvious to one of ordinary skill in the art to use the light sensitive Opn5 taught by Lucas in the claimed method of restoring light sensitivity to retinal cells. Lucas is directed to restoring photosensitivity and visual function in a degenerating retina and identified Opn5 as one of the potential proteins. Thus the claimed therapeutic use of a light sensitive Opn5 is not unobvious.
Regarding claim 26: Lucas disclosed expression of rhodopsin in RGC cells of retina when transduced by AAV (See [109]).
Regarding claim 28, 35: Lucas taught stimulation using a 410nm light (See [121]).
Regarding claim 36: Lucas taught intravitreal delivery of Opn5. (See [0007]).
Regarding claim 46: Claim 14 of Lucas taught AAV vector system for administration of their nucleic acid.
Claims 37 and 43 are rejected under 35 U.S.C. 103 as being unpatentable over Lucas et al (EP3578197A1; Published Dec 11, 2019; hereinafter "Lucas;" See PTO-892) as evidenced by Dai et al (Sci China Life Sci. 2022 Jul; hereinafter “Dai;” See IDS 05/10/2024), further in view of LeVaillant et al (Mol Ther Methods Clin Dev. 2016 Dec 7; hereinafter “LeVaillant;” See PTO-892).
Regarding claim 37 and 43: The teachings of Lucas as evidenced by Dai are set forth above. Lucas did not explicitly teach a reporter gene such as a fluorescent protein as part of their nucleic acid construct. LeVaillant described “[a]deno-associated viral (AAV) vectors encoding brain-derived neurotrophic factor (BDNF) or ciliary derived neurotrophic factor (CNTF) promote the viability and regeneration of injured adult rat retinal ganglion cells.” (See LeVaillant Abstract). In their study LeVaillant tagged their cargo (BDNF or CNTF) with a green fluorescent protein, which they used as a reporter. As such it was known prior to the filing of the instant application to use reporter assays to probe protein expression in cells, such as RGCs. Accordingly, a person of ordinary skill in the art would have has a reason to combine the teachings of Lucas and LeValliant to report AAV mediated transduction for monitoring and identifying gene expression.
Conclusion
Claims 31-34 appear free of art, but they lack written description and enablement.
No claim is 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.
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/JAGAMYA NMN VIJAYARAGHAVAN/ Examiner, Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633
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