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
The instant application is a continuation of international application PCT/US2022/026100, filed 25 April 2022. Acknowledgment is made of Applicant’s claim for benefit under 35 USC 119(e) to US Provisional Application No. 63/179753, filed 26 April 2021. Therefore, the effective filing date of the instant application is 26 April 2021.
Status of the Claims
Applicant’s preliminary submission filed 12 February 2024 has been entered. Claims 1-4, 6-7, 12, 15, 20, 35-36, 38-39, 44-45, 53-55, and 57-58 are pending. Claims 2, 4, 6-7, 12, 15, 20, 36, 39, 44-45, 53, 55, and 57 have been amended, while claims 5, 8-11, 13-14, 16-19, 21-34, 37, 40-43, 46-52, 56, and 59-62 have been cancelled without prejudice or disclaimer. Therefore, prosecution on the merits commences for claims 1-4, 6-7, 12, 15, 20, 35-36, 38-39, 44-45, 53-55, and 57-58.
Claim Objections
Claims 12, 15, 20, 38-39, and 44 are objected to because of the following informalities:
Regarding claim 12: The instant claim is objected to for using semicolons instead of commas within the Markush grouping. See MPEP § 2117.
Appropriate correction is required.
Regarding claims 15, 20, and 38-39: The instant claims are objected to for failing to consistently recite the limitations requiring a human Best1 promoter. More specifically, instant claims 15 and 38 each recite it as “a human Best1 promoter”, whereas instant claims 20 and 39 each recite it as “a human Best 1 promoter”. Applicant must select whether or not to include the space between “Best” and “1”, and then amend the claims such that the recitation is uniform throughout.
Appropriate correction is required.
Regarding claim 44: The instant claim is objected to for reciting “[t]he composition od of…”. Applicant must delete the recitation of “od” within the claim.
Appropriate correction is required.
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 1-4, 6-7, 12, 15, 20, 35-36, 38-39, 44-45, 53-55, and 57-58 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 inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims under rejection are directed to a method for treating or preventing a degenerative ocular disorder in a subject, comprising administering to the subject a therapeutically effective amount of an agent that enhances CD47-SIRPα signaling, thereby treating or preventing the degenerative ocular disorder in the subject.
With that, instant claim 12 further limits the agent that enhances CD47-SIRPα signaling:
wherein the agent prevents degeneration of a cone photoreceptors cell;
wherein the agent increases the expression and/or activity of CD47 and/or SIRPα;
wherein the agent is selected from the group consisting of a viral vector construct expressing CD47, an adeno-associated virus (AAV) expression cassette comprising a nucleic acid molecule encoding CD47; a small molecule activator of CD47; an anti-CD47 agonistic antibody or antigen-binding fragment thereof; a CD47 fusion protein; a CD47 protein or fragment thereof; an AAV expression cassette comprising a nucleic acid molecule encoding SIRPα; a small molecule activator of SIRPα; an anti- SIRPα agonistic antibody or antigen- binding fragment thereof; a SIRPα fusion protein; and a SIRPα protein or fragment thereof; and/or
wherein the agent is an AAV expression cassette comprising a nucleic acid molecule encoding CD47.
Thus, to satisfy the written description aspect of 35 U.S.C. 112(a) for a claimed group – or genus – of agents, MPEP §2163 recites, “[t]he written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus…when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus.”
The written description inquiry is limited to that which is contained within the four corners of the specification, not the extent to which the skilled artisan, given his or her knowledge of the art, would have considered it to expand with only routine experimentation. See Ariad Pharms. Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010); see also id. at 1352 (“[I]t is the specification itself that must demonstrate possession. . . . a description that merely renders the invention obvious does not satisfy the requirement.").
Regarding disclosure of identifying characteristics of the claimed agents, a review of the Specification fails to provide a definition of the structural characteristics the agents encompassed by the current claims must have. As such, Applicant has failed to identify any particular core chemical structure or function (along with a correlation between function and a specific conserved structure) of the agents; and thus one of ordinary skill in the art would not immediately envisage all possible agents, as currently claimed. Therefore, Applicant has not disclosed the identifying characteristics of the claimed agents.
More specifically, Applicant has disclosed in Page 18 of the Specification filed 12 February 2024 that “[t]he agents that enhance CD47-SIRPα signaling suitable for use in the methods of the present invention include any compounds or molecules that can increase the expression and/or activity of CD47 and/or SIRPα, for example, the mRNA expression and/or protein expression of CD47 and/or SIRPα; the mRNA and/or protein stability of CD47 and/or SIRPα; and/or the biological activity of CD47 and/or SIRPα. An agent can increase the expression and/or activity of CD47 and/or SIRPα either directly or indirectly.”
With that, the sections relevant to antibodies, small molecules, fusion proteins are all hypothetical, as recited in Pages 38-40 of the Specification filed 12 February 2024:
“B. Agonist Antibodies
In some embodiments, the agents that enhance CD47-SIRPa signaling for use in the methods of the present invention are agonist antibodies that can bind CD47 or SIRPα and increase the expression and/or activities of CD47 and/or SIRPα. Agonist antibodies can be identified, screened for (e.g., using phage display), or characterized for their physical/chemical properties and/or biological activities by various assays known in the art (see, for example, Antibodies: A Laboratory Manual, Second edition, Greenfield, ed., 2014). Binding specificity of an antibody for its antigen can be tested by known methods in the art such as ELISA, Western blot, or surface plasmon resonance.”
“C. Small Molecule Activators
Other agents that enhance CD47-SIRPa signaling for use in the methods of the present invention include small molecule activators that bind CD47 or SIRPα, and increase the expression and/or activities of CD47 and/or SIRPα. Such compounds can be either natural products or members of a combinatorial chemist1y library, and can be identified using screening assays, as described in detail below.”
“D. Fusion proteins or protein variants
In some embodiments, agents that enhance CD47-SIRPa signaling for use in the methods of the present invention also include variants of CD47 and/or SIRPα protein that can function as agonists and activate the activity of CD47 and/or SIRPα. For example, an agent suitable for use in the methods of the present invention is a full-length CD47 or SIRPα protein, or a fragment of CD47 or SIRPα. In some embodiments, an agent is a wild type CD47 and/or SIRPα protein. In other embodiments, a CD47 and/or SIRPα protein variant or fragment that has an increased activity would also function as an agent for use in the methods of the present invention.”
The courts have described the essential question to be addressed in a description requirement issue in a variety of ways. An objective standard for determining compliance with the written description requirement is, "does the description clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed." In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989). Under Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Fed. Cir. 1991), to satisfy the written description requirement, an 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, and that the invention, in that context, is whatever is now claimed. The test for sufficiency of support in a parent application is whether the disclosure of the application relied upon "reasonably conveys to the artisan that the inventor had possession at that time of the later claimed subject matter." Ralston Purina Co. v. Far-Mar-Co., Inc., 772 F.2d 1570, 1575, 227 USPQ 177, 179 (Fed. Cir. 1985) (quoting In re Kaslow, 707 F.2d 1366, 1375, 217 USPQ 1089, 1096 (Fed. Cir. 1983)). Whenever the issue arises, the fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Fed. Cir. 1991). See M.P.E.P. § 2163.02. In this case, the skilled artisan would not have reasonably concluded at the time of the invention that applicant was in possession of the entire invention as claimed.
Applicant’s disclosure also fails to provide a sufficient number of exemplary agents given the breadth of the genus. More specifically, Applicant has provided a single working example of administering “an agent”, wherein a specific gene is comprised within a specific AAV vector and administered to specific models. With that, the therapeutic amounts disclosed within the Specification only pertain to AAV vectors, which does not represent the entire scope of agents that is claimed. See Figure 2A and Pages 50, 56 (as shown below):
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The written description requirement is in place to ensure that “when a patent claims a genus by its function or result, the specification recites sufficient materials to accomplish that function.” Ariad Pharms. Co. v. Eli Lilly & Co., 94 U.S.P.Q.2d 1161, 1172 (Fed. Cir. 2010) (en banc). A consideration of the four corners of the Specification does not reflect that Applicant has actually invented the scope of the claimed invention, since the working examples are limited to a single AAV8 vector encoding a single CD47 protein, administered in a single way, in specific mouse models. However, the lone working example of an agent encompassed by the pending claims is not sufficient to fulfill the written description requirement for a sufficient description of a representative number of species, which is required to claim the entire genus of “an agent” that “enhances CD47-SIRPα signaling”, as required by the claims. Additionally, there is no disclosure of relevant, identifying characteristics, such as structure or other physical or chemical properties, or functional characteristics, beyond disclosure of the generic action (“enhances CD47-SIRPα signaling”), sufficient to show that Applicant was in possession of the claimed genus. See Eli Lilly, 119F. 3d. at 1568, 43 USPQ2d at 1406, and MPEP § 2163. Therefore, the Specification does not permit the skilled artisan to visualize all of the members of the genus being administered in the claimed methods.
If claims merely recite a “description of the problem to be solved while claiming all solutions to it” and “cover any compound later actually invented and determined to fall within the claim’s functional boundaries,” they have not met the description requirement. Ariad, 94 U.S.P.Q.2d at 1172.
Furthermore, the Examiner notes that the prior art in regards to the claims is unpredictable. More specifically, there are the inherent retinal architectural differences between humans and animals, as well as a corresponding potential for differing disease progression within those subjects. Trapani et al disclose that larger animals have more pronounced physical barriers than mice in regards to the retinal architecture, and thereby do not have the same treatment efficacy as within murine models. See Pages 194-195, “Safe and effective Delivery of Vectors to the Outer Retina: Are we there yet?”, of Trapani et al (Hum Gene Ther, 2015). With that, Thapa et al disclose that the efficacy of administered peptides differs given the gene therapy method. See Pages 2-3, “Peptides for gene delivery”, of Trapa et al (Curr Opin Biomed Eng, 2018).
Accordingly, Applicant’s disclosure appears to be an investigation of a mechanism wherein expression of CD47 protects cone photoreceptor cells within murine models. However, [p]atents are not awarded for academic theories, no matter how groundbreaking or necessary to the later patentable inventions of others.” Ariad, 94 U.S.P.Q.2d at 1173. The patent system is designed to give incentives to complete inventions, not to guess at the future. Id. at 1174.
Taken together, the lack of disclosure of species, lack of an established structure-function relationship in the Specification or prior art, and unpredictability of the prior art, a skilled artisan would not conclude that Applicant was in possession of the claimed invention. Accordingly, the claims are considered to lack sufficient written description and are properly rejected under 35 USC 112(a).
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 44-45 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.
Regarding claims 44-45: Instant claim 44 fails to list a claim from which it is dependent from.
Therefore, the ordinary artisan cannot readily determine the metes and bounds of the claim, thus rendering the scope of the claim indefinite. Instant claim 45 is included within this rejection because it is dependent upon instant claim 44.
Appropriate correction is required.
For the sake of compact prosecution, instant claim 44 will be interpreted as being dependent upon independent claim 35.
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 1-2, 6-7, 12, 15, 35, 38, 44, 53-55, and 57-58 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Nagy et al (US 2021/0161971 A1). Nagy et al has an effective filing date of 12 June 2017.
Nagy et al disclose cells that have been genetically modified to comprise a set of transgenes that
“cloaks” the cell from macrophage-mediated phagocytosis, wherein the set of transgenes includes CD47 (Paragraphs [0018]-[0022], [0031]-[0034], [0037], [0044]-[0047], [0054]-[0055], [0083]-[0092], [0105], [0127], [0149], [0154]-[0156], [210]-[0211], [0213]-[0214], [0239], [0346], [0362], [0376]; Examples 1-2, 8; Figures 1D, 8D, 16C, 19). Nagy et al further disclose that the transgenes are encoded and comprised within an AAV expression cassette, and are operably linked to a CMV or CAG promoter (Paragraphs [0179]-[0180], [0182], [0197]-[0205], [0223], [0249], [0346], [0378], [0389]; Figure 19; Example 13). Nagy et al further disclose that the AAV expression cassette is incorporated into an AAV virion, or vector particle, wherein the AAV virion has a serotype of AAV2 or AAV8 (Paragraphs [0201]-[0205]).
Nagy et al further disclose that the genetically modified cells are comprised within a pharmaceutical composition, which is administered through subretinal injection to a patient suffering from age-related macular generation (Paragraphs [0051]-[0053], [0069]-[0071], [0083], [0113]-[0114], [0222], [0239], [0295]-[0313], [0316], [0318]-[0319], [0324], [0389]-[0390]; Table 2; Example 13).
Nagy et al further disclose that the subject is a human subject (Paragraphs [0052], [0114], [0173], [0296], [0389]-[0390]; Example 13)
Accordingly, Nagy et al anticipate the claims as follows:
Regarding claims 1, 7, and 12: Nagy et al disclose a method of treating age-related macular degeneration (claim 7) in a subject, wherein a therapeutically effective amount of cloaked cells comprising an encoded CD47 transgene is administered to the subject. As the CD47 expression is greater within the cloaked cells compared to wildtype expression (claim 12) (Paragraphs [0054], [0211]), the CD47-SIRPα signaling will inherently be enhanced. See MPEP § 2112 and 2112.02. This therefore reads on the method of instant claim 1.
Regarding claim 2: Following the discussion of claim 1, Nagy et al further disclose that the administration of the cloaked cells to subjects suffering from age-related macular degeneration prevents the loss of functional vision (Paragraphs [0389]-[0390]; Example 13). This therefore reads on the method of the instant claim.
Regarding claim 6: Following the discussion of claim 6, Nagy et al further disclose that the subject is a human subject. This therefore reads on the method of the instant claim.
Regarding claim 15: Following the discussion of claim 12, Nagy et al further disclose that the encoded CD47 transgene is operably linked to a CMV or CAG promoter. This therefore reads on the method of the instant claim.
Regarding claims 35, 38, and 55: Nagy et al disclose a pharmaceutical composition (claim 55) that comprises cloaked cells, wherein the cloaked cells comprise an AAV expression cassette comprising a nucleic acid encoding a CD47 transgene that is operably linked to a CMV or CAG promoter (claim 38). This therefore reads on the composition of instant claim 35.
Regarding claim 44 and 53-54: Following the discussion of claim 35, Nagy et al further disclose that the AAV expression cassette is comprised within an AAV virion (claim 53) having a serotype of AAV2 or AAV8 (claim 44), which is then introduced into the isolated cells to be cloaked (claim 54). This therefore reads on the composition, AAV vector particle, and isolated cell of the instant claims.
Regarding claims 57-58: Following the discussion of claim 55, Nagy et al further disclose that the pharmaceutical composition is formulated for subretinal injection (claim 58). This therefore reads on the pharmaceutical composition of instant claim 57.
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 (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 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.
Claims 1-2, 6-7, 12, 15, 35-36, 38, 44, 53-55, and 57-58 are rejected under 35 U.S.C. 103 as being unpatentable over Nagy et al (US 2021/0161971 A1).
The discussion of Nagy et al regarding claim 35 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. Nagy et al anticipate claims 1-2, 6-7, 12, 15, 35, 38, 44, 53-55, and 57-58.
Regarding claim 36: Following the discussion of claim 35 above, Nagy et al further disclose that the CD47 transgene has a polypeptide sequence as detailed in SEQ ID NOs: 3-4 (Paragraph [0156]).
Nagy et al do not disclose the nucleic acid sequence that encodes for the CD47 transgene, nor that the nucleic acid sequence has at least about 85% identity to one of instant SEQ ID NOs: 1-8, as required by instant claim 36.
However, when the polynucleotide sequences of instant SEQ ID NO: 1 and instant SEQ ID NO: 4 are converted to amino acid sequences, they each respectively have 100% sequence identity to SEQ ID NO: 4 and SEQ ID NO: 3 of Nagy et al. See sequence alignment at end of document.
Therefore, it would have been prima facie obvious to have modified the composition of Nagy et al such that the CD47 transgene is encoded by the polynucleotide sequences as set forth in instant SEQ ID NO: 1 or instant SEQ ID NO: 4. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to utilize a polynucleotide sequence that translates into the known CD47 polypeptide sequences of Nagy et al, and would have had a reasonable expectation of success given that (i) the reverse-translation of amino acid sequences to nucleic acid sequences is well within the skillset of the ordinary artisan, and (ii) there is a finite number of nucleic acid sequences that translate into the CD47 polypeptide sequences of Nagy et al. See MPEP § 2143(I)(E) and MPEP § 2143(I)(G).
Consequently, Nagy et al render obvious a composition comprising an encoded CD47 transgene, wherein the nucleic acid sequence encoding for the CD47 transgene is set forth in instant SEQ ID NO: 1 or instant SEQ ID NO: 4. This therefore renders obvious the composition of the instant claim.
Claims 1-2, 6-7, 12, 15, 20, 35-36, 38-39, 44, 53-55, and 57-58 are rejected under 35 U.S.C. 103 as being unpatentable over Nagy et al (US 2021/0161971 A1) in view of Hwang et al (US 2016/0040185 A1).
The discussion of Nagy et al regarding claims 1, 12, 15, 35, and 38 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. Nagy et al anticipate claims 1-2, 6-7, 12, 15, 35, 38, 44, 53-55, and 57-58. Nagy et al render obvious claims 1-2, 6-7, 12, 15, 35-36, 38, 44, 53-55, and 57-58. Hwang et al is considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2).
Regarding claims 20 and 39: As aforementioned in the discussion of claims 15 and 38, Nagy et al disclose that the encoded CD47 transgene is operably linked to a CAG or CMV promoter.
Nagy et al do not disclose the nucleotide sequence for the CAG or CMV promoters, nor that the nucleic acid sequences have at least about 85% identity to one of instant SEQ ID NOs: 11-12, as required by instant claims 20 and 39.
Hwang et al, however, disclose a human CMV promoter operably linked to a gene of interest comprised within a recombinant AAV vector (Abstract; Paragraphs [0013], [0026], [0028], [0061]-[0063], [0065]-[0067]). Hwang et al further disclose that the CMV promoter has a nucleotide sequence as set forth in SEQ ID NO: 121, which has 100% sequence identity to instant SEQ ID NO: 11 (Paragraph [0019], [0031], [0049]; Table 1). See sequence alignment at end of document.
Therefore, it would have been prima facie obvious to have substituted the CMV promoter of Nagy et al with the CMV promoter of Hwang et al having a nucleotide sequence as set forth in SEQ ID NO: 121, as doing so would have been a simple substitution of one CMV promoter for another. See MPEP § 2143(I)(B). One of ordinary skill in the art before the effective filing date of the invention would have recognized that the CMV promoters are functionally comparable, as both are operably linked to a gene of interest and comprised within an AAV expression cassette, and thereby would have been able to substitute the promoters with predictable results.
Consequently, Nagy et al as modified by Hwang et al render obvious an encoded CD47 transgene that is operably linked to a CMV promoter having a nucleic acid sequence of instant SEQ ID NO: 11. This therefore renders obvious the method (claim 20) and composition (claim 39) of the instant claims.
Claims 1-2, 6-7, 12, 15, 35-36, 38, 44-45, 53-55, and 57-58 are rejected under 35 U.S.C. 103 as being unpatentable over Nagy et al (US 2021/0161971 A1) in view of Malik (US 2020/0255860 A1).
The discussion of Nagy et al regarding claims 35 and 44 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. Nagy et al anticipate claims 1-2, 6-7, 12, 15, 35, 38, 44, 53-55, and 57-58. Nagy et al render obvious claims 1-2, 6-7, 12, 15, 35-36, 38, 44, 53-55, and 57-58. Malik is considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2).
Regarding claim 45: Following the discussion of claim 44, Nagy et al further disclose that the AAV expression cassette may include a Woodchuck Posttranscriptional Regulatory Element (WPRE) (Paragraph [0185]).
Nagy et al do not disclose the nucleotide sequence for the WPRE sequence, nor that the nucleic acid sequence has at least about 85% identity to instant SEQ ID NOs: 15, as required by instant claim 45.
Malik, however, discloses post-transcriptional regulatory elements that are comprised within an AAV vector and enhance the expression of an encoded transgene (Paragraphs [0054], [0090], [0072]-[0073]). Malik further discloses that the post-transcriptional regulatory element is a WPRE sequence having a nucleotide sequence as set forth in SEQ ID NO: 12, which has 100% sequence identity to instant SEQ ID NO: 15 (Paragraphs [0072]-[0073]; Table 3). See sequence alignment at end of document.
Therefore, it would have been prima facie obvious to have substituted the WPRE sequence of Nagy et al with the WPRE sequence of Malik having a nucleotide sequence as set forth in SEQ ID NO: 12, as doing so would have been a simple substitution of one WPRE sequence for another. See MPEP § 2143(I)(B). One of ordinary skill in the art before the effective filing date of the invention would have recognized that the WPRE sequence are functionally comparable, as both are comprised within an AAV expression cassette, and thereby would have been able to substitute the WPRE sequences with predictable results.
Consequently, Nagy et al as modified by Malik render obvious an AAV expression cassette that further comprises a WPRE sequence having a nucleic acid sequence of instant SEQ ID NO: 15. This therefore renders obvious the composition of the instant claim.
Claims 3-4 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al (WO 2022/103766 A2) in view of Barclay et al (Annu Rev Immunol, 2013).
Liu et al is considered prior art under 35 USC 102(a)(2), with an effective filing date of 10 November 2020.
Regarding claim 3: Liu et al disclose compositions and methods comprising modified adeno-
associated virus (AAV) capsids, wherein the compositions are utilized as ocular therapeutics (Abstract).
As such, Liu et al disclose an AAV vector comprising the modified AAV capsid and a transgene, wherein the transgene is an anti-CD47 antibody or CD47 biologic for the treatment of a degenerative ocular disease (Paragraphs [0007], [0020], [0099]-[0105], [0125]).
Liu et al further disclose that the AAV vector comprising the CD47 transgene is delivered to a photoreceptor cell and results in an improvement in the health of the retinal anatomy, including the retinal photoreceptor cells (Paragraphs [0081]-[0083], [0099], [0110], [0128], [0132]).
Liu et al further disclose that the CD47 transgene expression is increased within the photoreceptor cells (Paragraphs [0007], [0019], [0100]).
Liu et al do not disclose that the CD47 biologic transgene enhances CD47-SIRPα signaling, as required by instant claim 3.
Barclay et al, however, disclose that CD47 is a membrane protein expressed on virtually all cell types and interacts with the myeloid inhibitory immunoreceptor SIRPα, wherein engagement of SIRPα by CD47 provides a downregulatory signal that inhibits host cell phagocytosis. Accordingly, CD47 functions as a “don’t-eat-me” signal for the cell (Pages 25-26, 28).
Therefore, it would have been prima facie obvious to have modified the method of Liu et al such that the administration of an AAV vector comprising the CD47 transgene to a compromised photoreceptor cell enhances CD47-SIRPα signaling within the cell, as detailed in Barclay et al. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to enhance CD47-SIRPα signaling via the CD47 transgene, as expression of the CD47 transgene allows the compromised photoreceptor cell to express the “don’t eat me” signal, thereby prolonging the viability of the compromised photoreceptor cell. Furthermore, the ordinary artisan would have had a reasonable expectation of success given that Liu et al teach both (i) the CD47 transgene and (ii) the restored health of retinal cells via the administration of other anti-apoptotic transgenes within embodiments of their invention (Paragraphs [0102], [0109]-[0110]). See MPEP § 2143(I)(G).
Consequently, Liu et al and modified by Barclay et al render obvious a method for prolonging the viability of a photoreceptor cell compromised by a degenerative ocular disorder, wherein the compromised photoreceptor cell is contacted with an AAV vector comprising a CD47 transgene. As the CD47 transgene enhances CD47-SIRPα signaling, this therefore renders obvious the method of the instant claim.
Regarding claim 4: Following the discussion of claim 3, Liu et al further disclose that the delivery of the AAV vector occurs either in vitro or in vivo (Paragraphs [0081], [0084], [0096], [0118]). This therefore reads on the method of the instant claim.
Conclusion
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/ALYSSA G WESTON/Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633
Sequence Alignment
Query Match 100.0%; Length 323; Matches 323; Mismatches 0; Gaps 0;
Qy 1 MWPLVAALLLGSACCGSAQLLFNKTKSVEFTFCNDTVVIPCFVTNMEAQNTTEVYVKWKF 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MWPLVAALLLGSACCGSAQLLFNKTKSVEFTFCNDTVVIPCFVTNMEAQNTTEVYVKWKF 60
Qy 61 KGRDIYTFDGALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 KGRDIYTFDGALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT 120
Qy 121 REGETIIELKYRVVSWFSPNENILIVIFPIFAILLFWGQFGIKTLKYRSGGMDEKTIALL 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 REGETIIELKYRVVSWFSPNENILIVIFPIFAILLFWGQFGIKTLKYRSGGMDEKTIALL 180
Qy 181 VAGLVITVIVIVGAILFVPGEYSLKNATGLGLIVTSTGILILLHYYVFSTAIGLTSFVIA 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 VAGLVITVIVIVGAILFVPGEYSLKNATGLGLIVTSTGILILLHYYVFSTAIGLTSFVIA 240
Qy 241 ILVIQVIAYILAVVGLSLCIAACIPMHGPLLISGLSILALAQLLGLVYMKFVASNQKTIQ 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 ILVIQVIAYILAVVGLSLCIAACIPMHGPLLISGLSILALAQLLGLVYMKFVASNQKTIQ 300
Qy 301 PPRKAVEEPLNAFKESKGMMNDE 323 (TRANSLATED INSTANT SEQ ID NO: 1)
|||||||||||||||||||||||
Db 301 PPRKAVEEPLNAFKESKGMMNDE 323 (NAGY ET AL SEQ ID NO: 4)
Query Match 100.0%; Length 303; Matches 303; Mismatches 0; Gaps 0;
Qy 1 MWPLAAALLLGSCCCGSAQLLFSNVNSIEFTSCNETVVIPCIVRNVEAQSTEEMFVKWKL 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MWPLAAALLLGSCCCGSAQLLFSNVNSIEFTSCNETVVIPCIVRNVEAQSTEEMFVKWKL 60
Qy 61 NKSYIFIYDGNKNSTTTDQNFTSAKISVSDLINGIASLKMDKRDAMVGNYTCEVTELSRE 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NKSYIFIYDGNKNSTTTDQNFTSAKISVSDLINGIASLKMDKRDAMVGNYTCEVTELSRE 120
Qy 121 GKTVIELKNRTVSWFSPNEKILIVIFPILAILLFWGKFGILTLKYKSSHTNKRIILLLVA 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GKTVIELKNRTVSWFSPNEKILIVIFPILAILLFWGKFGILTLKYKSSHTNKRIILLLVA 180
Qy 181 GLVLTVIVVVGAILLIPGEKPVKNASGLGLIVISTGILILLQYNVFMTAFGMTSFTIAIL 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 GLVLTVIVVVGAILLIPGEKPVKNASGLGLIVISTGILILLQYNVFMTAFGMTSFTIAIL 240
Qy 241 ITQVLGYVLALVGLCLCIMACEPVHGPLLISGLGIIALAELLGLVYMKFVASNQRTIQPP 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 ITQVLGYVLALVGLCLCIMACEPVHGPLLISGLGIIALAELLGLVYMKFVASNQRTIQPP 300
Qy 301 RNR 303 (TRANSLATED INSTANT SEQ ID NO: 4)
|||
Db 301 RNR 303 (NAGY ET AL SEQ ID NO: 3)
** TRANSLATION PROVIDED BY EXPASY TRANSLATE TOOL **
Query Match 100.0%; Length 584; Matches 584; Mismatches 0; Gaps 0;
Qy 1 GACATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCC 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 GACATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCC 60
Qy 61 CATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 CATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCA 120
Qy 121 ACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGA 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 ACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGA 180
Qy 181 CTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATC 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 CTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATC 240
Qy 241 AAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCT 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 AAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCT 300
Qy 301 GGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTAT 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 GGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTAT 360
Qy 361 TAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGC 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 TAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGC 420
Qy 421 GGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTT 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 GGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTT 480
Qy 481 GGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAA 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 GGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAA 540
Qy 541 TGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCT 584 (INSTANT SEQ ID NO: 11)
||||||||||||||||||||||||||||||||||||||||||||
Db 541 TGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCT 584 (HWANG SEQ ID NO: 121)
Query Match 100.0%; Length 583; Matches 542; Mismatches 0; Gaps 0;
Qy 1 AATCAACCTCTGGATTACAAAATTTGTGAAAGATTGACTGGTATTCTTAACTATGTTGCT 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 6 AATCAACCTCTGGATTACAAAATTTGTGAAAGATTGACTGGTATTCTTAACTATGTTGCT 65
Qy 61 CCTTTTACGCTATGTGGATACGCTGCTTTAATGCCTTTGTATCATGCTATTGCTTCCCGT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 66 CCTTTTACGCTATGTGGATACGCTGCTTTAATGCCTTTGTATCATGCTATTGCTTCCCGT 125
Qy 121 ATGGCTTTCATTTTCTCCTCCTTGTATAAATCCTGGTTGCTGTCTCTTTATGAGGAGTTG 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 126 ATGGCTTTCATTTTCTCCTCCTTGTATAAATCCTGGTTGCTGTCTCTTTATGAGGAGTTG 185
Qy 181 TGGCCCGTTGTCAGGCAACGTGGCGTGGTGTGCACTGTGTTTGCTGACGCAACCCCCACT 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 186 TGGCCCGTTGTCAGGCAACGTGGCGTGGTGTGCACTGTGTTTGCTGACGCAACCCCCACT 245
Qy 241 GGTTGGGGCATTGCCACCACCTGTCAGCTCCTTTCCGGGACTTTCGCTTTCCCCCTCCCT 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 246 GGTTGGGGCATTGCCACCACCTGTCAGCTCCTTTCCGGGACTTTCGCTTTCCCCCTCCCT 305
Qy 301 ATTGCCACGGCGGAACTCATCGCCGCCTGCCTTGCCCGCTGCTGGACAGGGGCTCGGCTG 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 306 ATTGCCACGGCGGAACTCATCGCCGCCTGCCTTGCCCGCTGCTGGACAGGGGCTCGGCTG 365
Qy 361 TTGGGCACTGACAATTCCGTGGTGTTGTCGGGGAAGCTGACGTCCTTTCCATGGCTGCTC 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 366 TTGGGCACTGACAATTCCGTGGTGTTGTCGGGGAAGCTGACGTCCTTTCCATGGCTGCTC 425
Qy 421 GCCTGTGTTGCCACCTGGATTCTGCGCGGGACGTCCTTCTGCTACGTCCCTTCGGCCCTC 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 426 GCCTGTGTTGCCACCTGGATTCTGCGCGGGACGTCCTTCTGCTACGTCCCTTCGGCCCTC 485
Qy 481 AATCCAGCGGACCTTCCTTCCCGCGGCCTGCTGCCGGCTCTGCGGCCTCTTCCGCGTCTT 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 486 AATCCAGCGGACCTTCCTTCCCGCGGCCTGCTGCCGGCTCTGCGGCCTCTTCCGCGTCTT 545
Qy 541 CG 542 (INSTANT SEQ ID NO: 15)
||
Db 546 CG 547 (MALIK SEQ ID NO: 12)