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 .
Detailed Action
This action is in response to the papers filed January 22, 2026.
Applicant has cancelled Claims 1-20, 39, 42, 44, 51, and 56, amended Claims 25, 33, 41, 43, and 49-50.
Claims 21-38, 40-41, 43, 45-50, 52-55, and 57-61 are pending and under consideration.
The finality of the prior Office Action mailed October 22, 2025 is withdrawn in light of Applicant’s argument that the instant claims are directed to a complement receptor 2 (CR2)-complement receptor 1 (CR1) fusion protein, not a CR2- complement factor H (FH) fusion protein, which upon reconsideration of the claims and the cited prior art, the Examiner finds persuasive.
Priority
This application is a continuation of application 16/351,289 filed on March 12, 2019, now abandoned. Applicant’s claim for the benefit of a prior-filed application provisional application 62/641,594 filed on March 12, 2018 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Claim Objections
1. The prior objections to Claims 25, 33, 41, 43, and 49-50 are withdrawn in light of Applicant’s amendments to the claims to identify the promoters by their complete names.
Double Patenting
2. The prior rejection of Claim 56 is objected to under 37 CFR 1.75 is withdrawn in light of Applicant’s cancellation of the claim.
Claim Rejections - 35 USC § 102
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.
3. The prior rejection of Claim(s) 21-22, 25-28, and 56-57 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gilkeson et al (U.S. Patent 9,212,212) is withdrawn in light of Applicant’s argument that the instant claims are directed to a CR2-CR1 fusion protein, not a CR2-FH fusion protein, which upon reconsideration of the claims, the Examiner finds persuasive.
4. Claim(s) 21, 25-28, and 57 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tomlinson et al (U.S. 2008/0267980), as evidenced by GenBank NP_001368780 (human complement receptor type 1, April 30, 2025).
Claim 21 is directed to a rAAV virus whose genome comprises a promoter operably linked to a nucleic acid encoding a CR2-CR1 fusion protein, wherein:
i) the CR2 portion comprises at least the SCR 1-2 domains of human complement receptor 2 (CR2) and is capable of binding one or more CR2 ligands selected from iC3b, C3dg, C3d, and a cell-bound fragment of C3b; and
ii) the CR1 portion comprises at least the SCR 1-2 domains of human complement receptor 1 and is capable of inhibiting complement activation.
With respect to Claim 21, Tomlinson et al is considered relevant prior art for having disclosed a rAAV virus (e.g. [0151, 161] whose genome comprises a promoter (e.g. [0162]) operably linked to a nucleic acid encoding a CR2-CR1 fusion protein (e.g. [0151], “CR2-CR1, CR1-CR2”).
Tomlinson et al disclosed the SCR 1-2 domains of complement receptor 2 (CR2) comprises the C3 binding site (e.g. [0009]), and thus is considered to be capable of binding one or more CR2 ligands selected from iC3b, C3dg, C3d, and a cell-bound fragment of C3b, absent objective evidence to the contrary.
Tomlinson et al disclosed the CR1 portion comprises at least SCR 1-2 domains of complement receptor 1 (CR1) (e.g. [0061-62, 69]) and thus is considered to be capable of inhibiting complement activation.
Tomlinson et al disclosed wherein the CR2 portion of the fusion protein is a human CR2 (e.g. [0313, 327, 332, 679, 681], “human CR2-complement inhibitor proteins”, “human CR2”).
Tomlinson et al disclose wherein the CR1 portion comprises the amino acid sequence of SEQ ID NO:14 (e.g. [0671]), which is a human CR1 amino acid sequence, as evidenced by GenBank NP_001368780.
Tomlinson et al does not disclose the rAAV capsid serotype; however, instant independent Claim 21 is considered non-limiting for the genus of AAV capsid serotypes per the recitation of “or a mutant capsid thereof”.
With respect to Claim 25, Tomlinson et al disclosed wherein the promoter is a CMV promoter and/or comprises the immediate early CMV promoter (e.g. [0182]).
With respect to Claim 26, Tomlinson et al disclosed wherein the CR2 portion comprises the first four SCR domains (e.g. [0054]).
With respect to Claim 57, Tomlinson et al disclosed wherein the CR1 portion comprises at least the first 8, 9, or 10 SCR domains (e.g. [0069]).
With respect to Claims 27-28, Tomlinson et al disclosed wherein a pharmaceutical composition comprising the rAAV encoding the CR2-CR1 fusion protein comprises a pharmaceutically acceptable carrier, e.g. saline (e.g. [0145]), for in vivo expression.
Instant claims fail to recite, and specification fails to disclose, a first pharmaceutical formulation comprising a pharmaceutically acceptable carrier that, while being suitable for administration to the eye (Claim 27), is not suitable for intraocular injection, subretinal injection, intravitreal injection, subscleral injection, or intrachoroidal injection (Claim 28), as opposed to a second pharmaceutical formulation comprising a pharmaceutically acceptable carrier that is not only suitable for administration to the eye (Claim 27), but also suitable for intraocular injection, subretinal injection, intravitreal injection, subscleral injection, or intrachoroidal injection (Claim 28). Absent objective evidence to the contrary, pharmaceutically acceptable carriers such as saline is/are considered to be suitable for intraocular injection, subretinal injection, intravitreal injection, subscleral injection, or intrachoroidal injection.
Thus, Tomlinson et al anticipate the claims.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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.
5. The prior rejection of Claims 21-22, 24-28, 41, and 56-57 under AIA 35 U.S.C. 103 as being unpatentable over Gilkeson et al (U.S. Patent 9,212,212), as applied to Claims 21-22, 25-28, and 56-57 above, and in further view of Ali et al (U.S. 2010/0081707) is withdrawn for reasons discussed above.
6. The prior rejection of Claims 22-23, 25, and 27-28 under AIA 35 U.S.C. 103 as being unpatentable over Gilkeson et al (U.S. Patent 9,212,212; of record), as applied to Claims 21-22, 25-28, and 56-57 above, and in further view of Mowat et al (Tyrosine capsid-mutant AAV vectors for gene delivery to the canine retina from a subretinal or intravitreal approach, Gene Therapy 21: 96-105, 2014) is withdrawn for reasons discussed above.
7. The prior rejection of Claims 29-31, 33-38, 40, 43, 45-50, and 52-61 under AIA 35 U.S.C. 103 as being unpatentable over Gilkeson et al (U.S. Patent 9,212,212; of record) in view of McFadden et al (U.S. 2016/0376325) and Ali et al (U.S. 2010/0081707; of record) is withdrawn for reasons discussed above.
8. The prior rejection of Claims 30, 32-35, 45-47, and 49 under AIA 35 U.S.C. 103 as being unpatentable over Gilkeson et al (U.S. Patent 9,212,212; of record) in view of McFadden et al (U.S. 2016/0376325; of record) and Ali et al (U.S. 2010/0081707; of record), as applied to Claims 29-31, 33-38, 40, 43, 45-50, and 52-61, and in further view of Mowat et al (Tyrosine capsid-mutant AAV vectors for gene delivery to the canine retina from a subretinal or intravitreal approach, Gene Therapy 21: 96-105, 2014; of record) is withdrawn for reasons discussed above.
9. Claims 21-22, 24-28, 41, and 57 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Tomlinson et al (U.S. 2008/0267980; of record), as evidenced by GenBank NP_001368780 (April 30, 2025; of record), as applied to Claims 21, 25-28, and 57 above, and in further view of Ali et al (U.S. 2010/0081707; of record) and Marsh et al (U.S. 2010/0130413).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Tomlinson et al disclosed wherein the promoter is a CMV promoter and/or comprises the immediate early CMV promoter (e.g. [0182]).
Tomlinson et al do not disclose wherein the rAAV the promoter is an RPE65 promoter.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim 41, Ali et al is considered relevant prior art for having disclosed rAAV expression vectors for the treatment of ocular disorders, e.g. age-related macular degeneration (e.g. [0008-9, 110]), wherein the therapeutic transgene of interest is operably linked to an RPE65 promoter (e.g. Figures 8, 9B; [0004]).
Marsh et al is considered relevant prior art for having disclosed the use of complement receptor 1 (CR1) for the treatment of macular degeneration, including age-relate macular degeneration (e.g. Abstract), whereby the pharmaceutical composition is administered to the eye of the subject (e.g. [0020]).
Resolving the level of ordinary skill in the pertinent art.
People of the ordinary skill in the art will be highly educated individuals such as medical doctors, scientists, or engineers possessing advanced degrees, including M.D.'s and Ph.D.'s. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in molecular biology, cloning, and viral vectors, including rAAV gene therapy vectors. Therefore, the level of ordinary skill in this art is high.
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at ___, 82 USPQ2d at 1396.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute a first promoter, e.g. a CMV promoter, as disclosed by Tomlinson et al, with a second promoter, i.e. an RPE65 promoter, as disclosed by Ali et al in a recombinant AAV expression vector encoding the artisan’s therapeutic transgene of interest for the treatment of an ocular disorder, e.g. macular degeneration, with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute a first promoter, e.g. a CMV promoter, with a second promoter, i.e. an RPE65 promoter, in a recombinant AAV expression vector encoding the artisan’s therapeutic transgene of interest for the treatment of an ocular disorder, e.g. macular degeneration, because Tomlinson et al disclosed the promoter may be a ubiquitous promoter, e.g. a CMV promoter, or a tissue-specific promoter, and Ali et al successfully demonstrated in a clinical trial the use of the human RPE65 promoter to drive expression of the artisan’s transgene of interest in the eyes of human patients.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claim 25, Tomlinson et al disclosed wherein the promoter is a CMV promoter and/or comprises the immediate early CMV promoter (e.g. [0182]).
With respect to Claim 26, Tomlinson et al disclosed wherein the CR2 portion comprises the first four SCR domains (e.g. [0054]).
With respect to Claim 57, Tomlinson et al disclosed wherein the CR1 portion comprises at least the first 8, 9, or 10 SCR domains (e.g. [0069]).
With respect to Claims 27-28, Tomlinson et al disclosed wherein a pharmaceutical composition comprising the rAAV encoding the CR2-CR1 fusion protein comprises a pharmaceutically acceptable carrier, e.g. saline (e.g. [0145]), for in vivo expression.
Ali et al disclosed wherein the pharmaceutical composition comprising the rAAV further comprises a pharmaceutically acceptable carrier (e.g. [0090]), e.g. saline ([0008, 91]) and is administered via subretinal or intravitreal injection (e.g. Figure 1; [0043, 91]; Example 2), whereby the subretinal rAAV administration was found to be safe in humans (e.g. [0134]).
Instant claims fail to recite, and specification fails to disclose, a first pharmaceutical formulation comprising a pharmaceutically acceptable carrier that, while being suitable for administration to the eye (Claim 27), is not suitable for intraocular injection, subretinal injection, intravitreal injection, subscleral injection, or intrachoroidal injection (Claim 28), as opposed to a second pharmaceutical formulation comprising a pharmaceutically acceptable carrier that is not only suitable for administration to the eye (Claim 27), but also suitable for intraocular injection, subretinal injection, intravitreal injection, subscleral injection, or intrachoroidal injection (Claim 28). Absent objective evidence to the contrary, pharmaceutically acceptable carriers such as saline is/are considered to be suitable for intraocular injection, subretinal injection, intravitreal injection, subscleral injection, or intrachoroidal injection.
With respect to Claims 22 and 24, Tomlinson et al disclosed a rAAV virus (e.g. [0151, 161].
Ali et al disclosed wherein the rAAV has an AAV2 capsid serotype (e.g. Example 2), or another capsid serotype, including, but not limited to AAV 5 and AAV8 (e.g. [0052]; claim 27).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
10. Claims 22-23, 25, and 27-28 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Tomlinson et al (U.S. 2008/0267980; of record), as evidenced by GenBank NP_001368780 (April 30, 2025; of record), as applied to Claims 21, 25-28, and 57 above, and in further view of Ali et al (U.S. 2010/0081707; of record) and Marsh et al (U.S. 2010/0130413; of record), as applied to Claims 21-22, 24-28, 41, and 57 above, and in further view of Mowat et al (2014; of record).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Tomlinson et al disclosed a rAAV virus (e.g. [0151, 161].
Ali et al disclosed wherein the rAAV has an AAV2 capsid serotype (e.g. Example 2), or another capsid serotype, including, but not limited to AAV 5 and AAV8 (e.g. [0052]; claim 27).
Neither Tomlinson et al nor Ali et al disclose wherein the rAAV2 capsid comprises a quadruple Y>F mutation.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim 23, Mowat et al is considered relevant prior art for having taught rAAV expression vectors for delivery of the artisan’s transgene of interest to the retina, wherein the AAV2 capsid has been modified to comprise four tyrosine-to-phenylalanine (syn. Y>F; quad Y-F) mutations, whereby the quad Y-F variant demonstrated a higher transduction efficiency of both outer and inner retinal cells (e.g. Abstract; pg 97, col. 1, “additional (Y>F) substitutions in AAV2 capsid further enhanced transduction efficiency”).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute a first AAV2 capsid, as disclosed by Tomlinson et al and/or Ali et al, with a second AAV2 capsid, i.e. comprising four Y>F mutations, as taught by Mowat et al in a recombinant AAV expression vector encoding the artisan’s therapeutic transgene of interest for the treatment of an ocular disorder, e.g. macular degeneration, with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute first AAV2 capsid with a second AAV2 capsid, i.e. comprising four Y>F mutations, in a recombinant AAV expression vector encoding the artisan’s therapeutic transgene of interest for the treatment of an ocular disorder, e.g. macular degeneration, because Mowat et al successfully demonstrated making such a substitution, and taught that the quad Y-F variant demonstrated a higher transduction efficiency of both outer and inner retinal cells (e.g. Abstract; pg 97, col. 1, “additional (Y>F) substitutions in AAV2 capsid further enhanced transduction efficiency”).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claim 25, Tomlinson et al disclosed wherein the promoter is a CMV promoter and/or comprises the immediate early CMV promoter (e.g. [0182]).
Mowat et al taught wherein the promoter comprises a chicken beta-actin promoter (e.g. pg 103, col. 1, Methods, Constructs).
With respect to Claims 27-28, Tomlinson et al disclosed wherein a pharmaceutical composition comprising the rAAV encoding the CR2-CR1 fusion protein comprises a pharmaceutically acceptable carrier, e.g. saline (e.g. [0145]), for in vivo expression.
Ali et al disclosed wherein the pharmaceutical composition comprising the rAAV further comprises a pharmaceutically acceptable carrier (e.g. [0090]), e.g. saline ([0008, 91]) and is administered via subretinal or intravitreal injection (e.g. Figure 1; [0043, 91]; Example 2), whereby the subretinal rAAV administration was found to be safe in humans (e.g. [0134]).
Mowat et al taught wherein the pharmaceutical composition comprising the rAAV further comprises a pharmaceutically acceptable carrier, e.g. sterile balanced salt solution, and is administered via subretinal or intravitreal injection (e.g. pg 103, col. 2, Methods, subretinal injections).
Instant claims fail to recite, and specification fails to disclose, a first pharmaceutical formulation comprising a pharmaceutically acceptable carrier that, while being suitable for administration to the eye (Claim 27), is not suitable for intraocular injection, subretinal injection, intravitreal injection, subscleral injection, or intrachoroidal injection (Claim 28), as opposed to a second pharmaceutical formulation comprising a pharmaceutically acceptable carrier that is not only suitable for administration to the eye (Claim 27), but also suitable for intraocular injection, subretinal injection, intravitreal injection, subscleral injection, or intrachoroidal injection (Claim 28). Absent objective evidence to the contrary, pharmaceutically acceptable carriers such as saline is/are considered to be suitable for intraocular injection, subretinal injection, intravitreal injection, subscleral injection, or intrachoroidal injection.
With respect to Claims 22 and 24, Tomlinson et al disclosed a rAAV virus (e.g. [0151, 161].
Ali et al disclosed wherein the rAAV has an AAV2 capsid serotype (e.g. Example 2), or another capsid serotype, including, but not limited to AAV 5 and AAV8 (e.g. [0052]; claim 27).
Mowat et al taught wherein the rAAV has an AAV2 capsid serotype or a mutant AAV2 capsid serotype (entire paper).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
11. Claims 29-31, 33-38, 40, 43, 45-50, and 52-61 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Tomlinson et al (U.S. 2008/0267980; of record) in view of Marsh et al (U.S. 2010/0130413; of record), Thurman et al (U.S. 2011/0229497), Ali et al (U.S. 2010/0081707; of record), and McFadden et al (U.S. 2016/0376325; of record).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
With respect to Claims 29 and 40, Tomlinson et al is considered relevant prior art for having disclosed a rAAV virus (e.g. [0151, 161] whose genome comprises a promoter (e.g. [0162]) operably linked to a nucleic acid encoding a CR2-CR1 fusion protein (e.g. [0151], “CR2-CR1, CR1-CR2”).
Tomlinson et al disclosed the SCR 1-2 domains of complement receptor 2 (CR2) comprises the C3 binding site (e.g. [0009]), and thus is considered to be capable of binding one or more CR2 ligands selected from iC3b, C3dg, C3d, and a cell-bound fragment of C3b, absent objective evidence to the contrary.
Tomlinson et al disclosed the CR1 portion comprises at least SCR 1-2 domains of complement receptor 1 (CR1) (e.g. [0061-62, 69]) and thus is considered to be capable of inhibiting complement activation.
Tomlinson et al disclosed wherein the CR2 portion of the fusion protein is a human CR2 (e.g. [0313, 327, 332, 679, 681], “human CR2-complement inhibitor proteins”, “human CR2”).
Tomlinson et al disclose wherein the CR1 portion comprises the amino acid sequence of SEQ ID NO:14 (e.g. [0671]), which is a human CR1 amino acid sequence, as discussed above.
Tomlinson et al does not disclose the rAAV capsid serotype; however, instant independent Claim 21 is considered non-limiting for the genus of AAV capsid serotypes per the recitation of “or a mutant capsid thereof”.
Tomlinson et al disclosed the pharmaceutical composition is used for the treatment of inflammatory conditions comprising complement activation and disease (e.g. Abstract).
Tomlinson et al do not disclose wherein the inflammatory conditions comprising complement activation and disease comprises an ocular disorder (Claim 40), more specifically macular degeneration (Claim 29).
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claims 29 and 40, Marsh et al is considered relevant prior art for having disclosed the use of complement receptor 1 (CR1) for the treatment of macular degeneration, including age-relate macular degeneration (e.g. Abstract), whereby the pharmaceutical composition is administered to the eye of the subject (e.g. [0020]).
Similarly, Thurman et al is considered relevant prior art for having disclosed the use of fusion proteins comprising complement receptor 1 (CR1) (e.g. [0010]) for the treatment of macular degeneration, including age-relate macular degeneration (e.g. [0018]), whereby the pharmaceutical composition is administered to the eye of the subject (e.g. [00223], “subretinal injection”).
Neither Tomlinson et al, Marsh et al, nor Thurman et al disclose wherein the rAAV is administered to the eye at a dose of least 1x10^9, or more, recombinant adeno-associated virus (AAV) vectors.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claims 29 and 40, Ali et al is considered relevant prior art for having disclosed rAAV expression vectors for the treatment of ocular disorders, e.g. age-related macular degeneration (e.g. [0008-9, 110]), wherein the therapeutic transgene of interest is operably linked to an RPE65 promoter (e.g. Figures 8, 9B; [0004]), wherein the number of vector particles administered per injection is about 1x10^6 to about 1x10^14 particles, preferably 1x10^7 to 1x10^13 particles, even more preferably 1x10^9 to 1x10^12 particles (e.g. [0103]). Ali et al disclosed administering 1x10^11 rAAV virus particles to the eye of a human subject (e.g. Example 2, [0131]).
Similarly, McFadden et al is considered relevant prior art for having disclosed a method of treating macular degeneration in a subject (e.g. Abstract), the method comprising the step(s) of administering to the subject’s eye a pharmaceutical composition comprising an rAAV gene therapy vector, wherein at least 1x10^9, more specifically 3x10^9, rAAV vector genomes were delivered to the eye (e.g. [0170]).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to modify the method of Tomlinson et al to comprise the step of administering at least 1x10^9 rAAV viral genomes to the eye of a human, dog, or cat subject with a reasonable expectation of success because those of ordinary skill in the art previously recognized and successfully reduced to practice administering at least 1x10^9 rAAV vectors to the eye of the artisan’s subject of interest, including human subjects (McFadden et al; Ali et al).
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claims 58 and 60, Tomlinson et al disclosed wherein the CR2 portion comprises the first four SCR domains (e.g. [0054]).
With respect to Claims 59 and 61, Tomlinson et al disclosed wherein the CR1 portion comprises at least the first 8, 9, or 10 SCR domains (e.g. [0069]).
With respect to Claims 33, 41, 43, and 49-50, Tomlinson et al disclosed wherein the promoter is a CMV promoter and/or comprises the immediate early CMV promoter (e.g. [0182]).
Ali et al disclosed wherein the therapeutic transgene of interest is operably linked to an RPE65 promoter (e.g. Figures 8, 9B; [0004]).
McFadden et al disclosed wherein the promoter comprises a chicken beta-actin promoter (Figure 3A; [0168]).
With respect to Claims 30-31 and 46-48, Tomlinson et al disclosed a rAAV virus (e.g. [0151, 161].
Ali et al disclosed wherein the rAAV has an AAV2 capsid serotype (e.g. Example 2), or another capsid serotype, including, but not limited to AAV 5 and AAV8 (e.g. [0052]; claim 27).
McFadden et al disclosed wherein the rAAV has an AAV2, AAV5, or AAV8 capsid serotype (e.g. [0024]).
With respect to Claims 36 and 55, Gilkeson et al disclosed wherein the macular degeneration includes age-related macular degeneration (e.g. claim 16).
McFadden et al disclosed wherein the macular degeneration includes age-related macular degeneration (e.g. Abstract).
Ali et al disclosed wherein the macular degeneration includes age-related macular degeneration (e.g. [0008]).
With respect to Claims 37-38, McFadden et al disclosed wherein the macular degeneration includes age-related macular degeneration, including both wet and dry forms (e.g. Abstract; [0068, 134]; claims 30 and 38).
Ali et al disclosed wherein the age-related macular degeneration includes neovascular (syn. wet) AMD (e.g. [0008]).
With respect to Claims 34-35, 45, and 52-54, Ali et al disclosed wherein the pharmaceutical composition comprising the rAAV further comprises a pharmaceutically acceptable carrier (e.g. [0090]), e.g. saline ([0008, 91]) and is administered via subretinal or intravitreal injection (e.g. Figure 1; [0043, 91]; Example 2), whereby the subretinal rAAV administration was found to be safe in humans (e.g. [0134]).
Thurman et al disclosed wherein the pharmaceutical composition is administered via subretinal, subscleral, or intravitreal injection (e.g. [0223]).
McFadden et al disclosed wherein the pharmaceutical composition is administered via subretinal, or intravitreal injection (e.g. claims 33 and 41).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
12. Claims 30-35, 41, 43, 45-50, and 52-54 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Tomlinson et al (U.S. 2008/0267980; of record) in view of Marsh et al (U.S. 2010/0130413; of record), Thurman et al (U.S. 2011/0229497; of record), Ali et al (U.S. 2010/0081707; of record), and McFadden et al (U.S. 2016/0376325; of record), as applied to Claims 29-31, 33-38, 40, 43, 45-50, and 52-61 above, and in further view of Mowat et al (2014; of record).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Neither Gilkeson et al, McFadden et al, or Ali et al disclose wherein the rAAV2 capsid comprises a quadruple Y>F mutation.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim 32, Mowat et al is considered relevant prior art for having taught rAAV expression vectors for delivery of the artisan’s transgene of interest to the retina, wherein the AAV2 capsid has been modified to comprise four tyrosine-to-phenylalanine (syn. Y>F; quad Y-F) mutations, whereby the quad Y-F variant demonstrated a higher transduction efficiency of both outer and inner retinal cells (e.g. Abstract; pg 97, col. 1, “additional (Y>F) substitutions in AAV2 capsid further enhanced transduction efficiency”).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute a first AAV2 capsid, as disclosed by Gilkeson et al, McFadden et al, and/or Ali et al, with a second AAV2 capsid, i.e. comprising four Y>F mutations, as taught by Mowat et al in a recombinant AAV expression vector encoding the artisan’s therapeutic transgene of interest for the treatment of an ocular disorder, e.g. macular degeneration, with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute first AAV2 capsid with a second AAV2 capsid, i.e. comprising four Y>F mutations, in a recombinant AAV expression vector encoding the artisan’s therapeutic transgene of interest for the treatment of an ocular disorder, e.g. macular degeneration, because Mowat et al successfully demonstrated making such a substitution, and taught that the quad Y-F variant demonstrated a higher transduction efficiency of both outer and inner retinal cells (e.g. Abstract; pg 97, col. 1, “additional (Y>F) substitutions in AAV2 capsid further enhanced transduction efficiency”).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claims 30-31 and 46-48, Tomlinson et al disclosed a rAAV virus (e.g. [0151, 161].
Ali et al disclosed wherein the rAAV has an AAV2 capsid serotype (e.g. Example 2), or another capsid serotype, including, but not limited to AAV 5 and AAV8 (e.g. [0052]; claim 27).
McFadden et al disclosed wherein the rAAV has an AAV2, AAV5, or AAV8 capsid serotype (e.g. [0024]).
Mowat et al taught wherein the rAAV has an AAV2 capsid serotype or a mutant AAV2 capsid serotype (entire paper).
With respect to Claims 33, 41, 43, and 49-50, Tomlinson et al disclosed wherein the promoter is a CMV promoter and/or comprises the immediate early CMV promoter (e.g. [0182]).
Ali et al disclosed wherein the therapeutic transgene of interest is operably linked to an RPE65 promoter (e.g. Figures 8, 9B; [0004]).
McFadden et al disclosed wherein the promoter comprises a chicken beta-actin promoter (Figure 3A; [0168]).
Mowat et al taught wherein the promoter comprises a chicken beta-actin promoter (e.g. pg 103, col. 1, Methods, Constructs).
With respect to Claims 34-35, 45, and 52-54, Ali et al disclosed wherein the pharmaceutical composition comprising the rAAV further comprises a pharmaceutically acceptable carrier (e.g. [0090]), e.g. saline ([0008, 91]) and is administered via subretinal or intravitreal injection (e.g. Figure 1; [0043, 91]; Example 2), whereby the subretinal rAAV administration was found to be safe in humans (e.g. [0134]).
Thurman et al disclosed wherein the pharmaceutical composition is administered via subretinal, subscleral, or intravitreal injection (e.g. [0223]).
McFadden et al disclosed wherein the pharmaceutical composition is administered via subretinal, or intravitreal injection (e.g. claims 33 and 41).
Mowat et al taught subretinal and invitreal injection of the rAAV virus particles (e.g. pg 103, col. 2, Methods, injections).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Conclusion
13. No claims are allowed.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638