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 June 30, 2026.
Applicant has cancelled Claims 1-20, 23, 32, 39, 42, 44, 46, 51, and 56, and amended Claims 21, 29-31, 40, 47-48, and 57.
Claims 21-22, 24-31, 32-38, 40-41, 43, 45, 47-50, 52-55, and 57-61 are pending and under consideration.
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.
Information Disclosure Statement
Applicant has filed an Information Disclosure Statement on June 30, 2026 that has been considered.
The information disclosure statement filed June 30, 2026 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because 37 CFR 1.98(b) requires that each item of information in an IDS be identified properly. Each publication must be identified by publisher, author (if any), title, relevant pages of the publication, and date and place of publication. The date of publication supplied must include at least the month and year of publication, except that the year of publication (without the month) will be accepted if the applicant points out in the information disclosure statement that the year of publication is sufficiently earlier than the effective U.S. filing date and any foreign priority date so that the particular month of publication is not in issue.
See also MPEP 707.05(e) for electronic documents, including, but not limited to:
(D) reference to the unique Digital Object Identifier (DOI) number, or other unique identification number, if known.
NPL citation 3 has been lined through for being defective of one or more requirements.
The signed and initialed PTO Forms 1449 are mailed with this action.
Claim Rejections - 35 USC § 102
1. The prior rejection of Claim(s) 21, 25-28, and 57 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et al (U.S. 2008/0267980), as evidenced by GenBank NP_001368780 (human complement receptor type 1, April 30, 2025) is withdrawn in light of Applicant’s amendments to the independent claims to recite the rAAV vector comprises an AAV2, AAV5, or AAV8 serotype capsid, a limitation Tomlinson et al do not disclose.
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.
2. The prior rejection of Claims 22-23, 25, and 27-28 under AIA 35 U.S.C. 103 as being unpatentable over Tomlinson et al (U.S. 2008/0267980; of record) in view of GenBank NP_001368780 (April 30, 2025; of record), Ali et al (U.S. 2010/0081707; of record), Marsh et al (U.S. 2010/0130413; of record), and Mowat et al (2014; of record) is withdrawn in light of Applicant’s cancellation of claims reciting Y to F AAV2 capsid variant (prior Claims 23 and 32).
3. The prior rejection of Claims 30-35, 41, 43, 45-50, and 52-54 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), McFadden et al (U.S. 2016/0376325; of record), and Mowat et al (2014; of record) is withdrawn in light of Applicant’s cancellation of claims reciting Y to F AAV2 capsid variant (prior Claims 23 and 32).
[Product]
4. 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), in view of GenBank NP_001368780 (April 30, 2025; of record), Ali et al (U.S. 2010/0081707; of record), and Marsh et al (U.S. 2010/0130413; of record).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
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:
i) the rAAV capsid serotype is AAV2, AAV5, or AAV8; nor
ii) the promoter is an RPE65 promoter.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claims 21 and 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]).
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 AAV5 and AAV8 (e.g. [0052]; claim 27).
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.
Prior to the effective filing date of the instantly claimed invention, it also would have been obvious to one of ordinary skill in the art to substitute a first rAAV capsid serotype for an AAV2, AAV5 or AAV8 capsid serotype, 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 rAAV capsid serotype for an AAV2, AAV5 or AAV8 capsid serotype, 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, because Ali et al successfully demonstrated in a clinical trial the use of a rAAV gene therapy for the treatment of retinal degeneration, wherein the rAAV comprises an AAV2 capsid serotype and an RPE65 promoter operably linked to the therapeutic transgene (e.g. Example 2, [0131]).
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.
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.
Response to Arguments
Applicant argues that Tomlinson at best provides a broad and general mention of AAV vectors without sufficient direction or guidance for how to make or use any specific AAV vectors. In particular, Tomlinson only discloses AAV generically in the detailed description among over 10 different vectors. The cited references would not have provided a skilled person in the art of successfully achieving the claimed invention with a reasonable expectation of success.
Applicant’s argument(s) has been fully considered, but is not persuasive.
The specification need not contain an example if the invention is otherwise disclosed in such manner that one skilled in the art will be able to practice it without an undue amount of experimentation. In re Borkowski, 422 F.2d 904, 908, 164 USPQ 642, 645 (CCPA 1970).
A reference contains an "enabling disclosure" if the public was in possession of the claimed invention before the date of invention. "Such possession is effected if one of ordinary skill in the art could have combined the publication's description of the invention with his [or her] own knowledge to make the claimed invention." In re Donohue, 766 F.2d 531, 226 USPQ 619 (Fed. Cir. 1985).
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Tomlinson et al clearly disclosed CR2-CR1 fusion proteins, thus making and using CR2-CR1 fusion proteins is/are not a novel or nonobvious scientific and/or technical concept.
Tomlinson et al clearly disclosed that those of ordinary skill in the art previously recognized rAAV viral vectors (e.g. [0099], “each and every viral vector known in the art”).
Ali et al successfully demonstrated the ability to synthesize a rAAV gene therapy vector comprising an AAV2 capsid serotype and a RPE65 promoter operably linked to the therapeutic transgene (e.g. Example 2, [0131]).
Molecular biology and rAAV expression vectors is/are an old art (1980’s technology), whereby the art is replete with successful reductions to practice, readily identified via a simple internet search of “recombinant AAV viral vectors”, for example:
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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.
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).
Thus, no undue experimentation is required.
Applicant provides no objective evidence to the contrary.
Applicant argues that Tomlinson lists at least 235 fusion proteins without any guidance suggesting selection of CR2-CR1.
Applicant’s argument(s) has been fully considered, but is not persuasive. The list of said 235 fusion proteins generally follows the variation on the theme of a smaller subgenus of about 10 fusion proteins (e.g. [0437-447]), whereby the CR2 may be the complete CR2, CR2 (SCR1-2), (SCR1-3), or (SCR1-4), for example. Tomlinson et al clearly disclosed and/or reduced to practice CR2-CR1 fusion proteins (e.g. [0378, 437, 463]). The list of fusion protein variants is not so great to prohibit the ordinary artisan from envisioning the genus of CR2-CR1 fusion proteins presently claimed as an embodiment.
Applicant argues that Tomlinson is directed to fusion proteins, not AAV vectors encoding said fusion proteins.
Applicant’s argument(s) has been fully considered, but is not persuasive.
The specification need not contain an example if the invention is otherwise disclosed in such manner that one skilled in the art will be able to practice it without an undue amount of experimentation. In re Borkowski, 422 F.2d 904, 908, 164 USPQ 642, 645 (CCPA 1970).
A reference contains an "enabling disclosure" if the public was in possession of the claimed invention before the date of invention. "Such possession is effected if one of ordinary skill in the art could have combined the publication's description of the invention with his [or her] own knowledge to make the claimed invention." In re Donohue, 766 F.2d 531, 226 USPQ 619 (Fed. Cir. 1985).
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Tomlinson et al clearly disclosed CR2-CR1 fusion proteins, thus making and using CR2-CR1 fusion proteins is/are not a novel or nonobvious scientific and/or technical concept.
Tomlinson et al clearly disclosed that those of ordinary skill in the art previously recognized rAAV viral vectors (e.g. [0099], “each and every viral vector known in the art”).
Ali et al successfully demonstrated the ability to synthesize a rAAV gene therapy vector comprising an AAV2 capsid serotype and a RPE65 promoter operably linked to the therapeutic transgene (e.g. Example 2, [0131]).
Thus, no undue experimentation is required.
Applicant provides no objective evidence to the contrary.
Applicant argues that Marsh is silent to rAAV.
Applicant’s argument(s) has been fully considered, but is not persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Tomlinson et al clearly disclosed CR2-CR1 fusion proteins, wherein said fusion proteins may be expressed from an rAAV expression vector.
Ali et al successfully demonstrated the ability to synthesize a rAAV gene therapy vector comprising an AAV2 capsid serotype and a RPE65 promoter operably linked to the therapeutic transgene (e.g. Example 2, [0131]).
Marsh et al disclosed that complement receptor 1 (CR1) proteins are useful for the treatment of retinal diseases and disorders.
Applicant argues that Ali is silent to CR2-CR1 fusion proteins.
Applicant’s argument(s) has been fully considered, but is not persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Tomlinson et al clearly disclosed CR2-CR1 fusion proteins, wherein said fusion proteins may be expressed from an rAAV expression vector.
Ali et al successfully demonstrated the ability to synthesize a rAAV gene therapy vector comprising an AAV2 capsid serotype and a RPE65 promoter operably linked to the therapeutic transgene (e.g. Example 2, [0131]).
Marsh et al disclosed that complement receptor 1 (CR1) proteins are useful for the treatment of retinal diseases and disorders.
[Method(s) of Use]
5. Claims 29-31, 33-38, 40, 43, 45, 47-50, 52-55, and 58-61 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; of record), 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]).
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]).
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 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.
Response to Arguments
Applicant argues that the Examiner has exercised impermissible hindsight.
Applicant’s argument(s) has been fully considered, but is not persuasive. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Tomlinson et al clearly disclosed CR2-CR1 fusion proteins, wherein said fusion proteins are useful therapeutics for the treatment of pathological conditions associated with complement activation (e.g. Abstract), and wherein said fusion proteins may be expressed from an rAAV expression vector.
Ali et al successfully demonstrated the ability to synthesize a rAAV gene therapy vector comprising an AAV2 capsid serotype and a RPE65 promoter operably linked to the therapeutic transgene to thereby treat a retinal disease/disorder (e.g. Example 2, [0131]).
Marsh et al disclosed that complement receptor 1 (CR1) proteins are useful for the treatment of retinal diseases and disorders.
Applicant argues that the specification discloses the rAAV-CR2-Crry fusion protein is able to treat mouse subjects to reduce progression of glaucoma.
Applicant’s argument(s) has been fully considered, but is not persuasive.
As a first matter, Applicant’s asserted secondary consideration was achieved using a rAAV packaged with an AAV2 triple YF mutant capsid, said rAAV vector comprising a CBA promoter to drive expression of the CR2-Crry fusion protein (pg 46, lines 6-12).
The ordinary artisan would immediately recognize that instant independent claims are vastly broader in scope than the asserted secondary consideration.
As a second matter, Applicant’s asserted secondary consideration was achieved with a CR2-Crry fusion protein, wherein said CR2 fusion protein comprises the amino acid sequence of SEQ ID NO:39 (768nts = 256aa) and the Crry protein comprises the amino acid sequence of SEQ ID NO:41 (encodes 319aa) (fusion protein SIN:42 = 610aa) (e.g. pg 12, lines 26-32; Figures 21A and 22A-B; pg 46, line 6, “CR2-Crry was utilized (see Fig. 22)”).
However, the claims encompass a genus of structurally different CR2-CR1 fusion proteins per “the CR2-CR1 fusion protein comprises…”. The term "comprises" is open-ended and allows for additional, unrecited elements in the claims. MPEP 2111.03 specifically sets forth that the transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004). The claims encompass fusion proteins comprising CR2 proteins comprising SCR1-4 domains and CR1 protein comprising SCR1-18 domains.
The ordinary artisan would immediately recognize that instant independent claims are vastly broader in scope than the asserted secondary consideration.
Applicant provides no objective evidence that the asserted secondary considerations achieved using the CR2 (at best just SCR1-2)-Crry (at best just SCR1-5) fusion protein would predictably extend over the genus of structurally and functionally different fusion proteins encompassed by the independent claims, and claims dependent therefrom, e.g. fusion proteins such as CR2 (SCR1-4)-CR1 (SCR1-18, and C1q binding site; 2048 amino acids (per Tomlinson et al, SEQ ID NO:14)).
Applicant argues that none of the cited references teach/disclose the claimed genus of CR2-CR1 fusion proteins would achieve the results Applicant achieved in the treated mice, to wit:
i) maintained 38% (10 months) and 40% (12 months) more healthy optic nerves compared with naïve mice;
ii) showed 34% (10 months) and 57% (12 months) fewer severely damaged nerves at each age when compared with naïve mice; and/or
iii) less Retinal Ganglion Cell loss as measured by 84% higher Bm3b-nucleic density at 10 months and 168% at 12 months when compared to naïve mice.
Applicant’s argument(s) has been fully considered, but is not persuasive. In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e. phenotypic result(s) above observed 10-12 months after administration) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). All that is required by the claims is to achieve some modicum of treatment, however minor that result might be.
Tomlinson et al clearly disclosed CR2-CR1 fusion proteins, wherein said fusion proteins are useful therapeutics for the treatment of pathological conditions associated with complement activation (e.g. Abstract), and wherein said fusion proteins may be expressed from an rAAV expression vector.
Ali et al successfully demonstrated the ability to synthesize a rAAV gene therapy vector comprising an AAV2 capsid serotype and a RPE65 promoter operably linked to the therapeutic transgene to thereby treat a retinal disease/disorder (e.g. Example 2, [0131]).
Marsh et al disclosed that complement receptor 1 (CR1) proteins are useful for the treatment of retinal diseases and disorders.
Applicant argues that Thurman and McFadden are directed to a completely different fusion protein than the present invention.
Applicant’s argument(s) has been fully considered, but is not persuasive.
The Examiner must determine what is "analogous prior art" for the purpose of analyzing the obviousness of the subject matter at issue. **>"Under the correct analysis, any need or problem known in the field of endeavor at the time of the invention and addressed by the patent [or application at issue] can provide a reason for combining the elements in the manner claimed. " KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1397 (2007). Thus a reference in a field different from that of applicant's endeavor may be reasonably pertinent if it is one which, because of the matter with which it deals, logically would have commended itself to an inventor's attention in considering his or her invention as a whole.<
Tomlinson et al clearly disclosed CR2-CR1 fusion proteins, thus making and using CR2-CR1 fusion proteins is/are not a novel or nonobvious scientific and/or technical concept.
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”).
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]).
Applicant is reminded that the cited references should not be read in a vacuum. 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.
Conclusion
6. No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638
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