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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on November 20, 2025 has been entered.
Detailed Action
This action is in response to the papers filed November 20, 2025.
Amendments
Applicant's response and amendments, filed November 20, 2025 and April 25, 2025, to the prior Office Action is acknowledged. Applicant has cancelled Claims 2-4, 6-9, 11-18, 20, 22-23, and 25-27, and amended Claims 1, 10, and 19.
Claims 1, 5, 10, 19, 21, and 24 are pending and under examination.
Priority
This application is a 371 of PCT/US2019/049850 filed on September 6, 2019. Applicant’s claim for the benefit of a prior-filed application provisional application 62/728,760 filed on September 8, 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 November 20, 2025 that has been considered.
The signed and initialed PTO Forms 1449 are mailed with this action.
Specification
The amendment filed November 20, 2025 to the Abstract is accepted.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
2. Claims 1, 5, 10, 19, 21, and 24 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Applicant has amended independent Claim 1 to recite “a functional vWF gene”, which is a relative term which renders the claim indefinite. The phrase “a functional vWF gene” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. “Functional” to do what??
Haberichter (von Willebrand factor propeptide: biology and clinical utility, Blood 126(15): 1753-1761, 2015) is considered relevant prior art for having taught that the vWF gene encodes a multi-functional protein comprising a multitude of different functional domains (e.g. Figure 1b-c).
Hassan et al (Structure and function of von Willebrand factor: the protein that is deficient and/or abnormal in inherited von Willebrand disease, Blood Coagul. Fibrinolysis 23: 11-22, 2011) is considered relevant prior art for having taught that the vWF gene encodes a multi-functional protein comprising a multitude of different functional domains (e.g. Table 1).
The recitation implies a genus of undisclosed phenotypes by which “a functional vWF gene” is to be determined and/or identified, thereby rendering the claim indefinite. A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
If there are multiple ways to measure “functional”, to wit, yet each yields a different result, then the claim may be indefinite because it is unclear which method is to be performed to determine infringement.
The instant claims as a whole do not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
3. Claims 5, 10, and 19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 5 recites the limitation “the von Willebrand factor gene”. There is insufficient antecedent basis for this limitation in the claim because Claim 1 recites a first vWF gene (lines 1-2), a second vWF gene (lines 9 and 11), and a third vWF gene (lines 14 and 16).
Claims 10 and 19 recite the limitation “the transgene”. There is insufficient antecedent basis for this limitation in the claim because Claim 1 recites a first vWF transgene (lines 9 and 11), and a second vWF transgene (lines 14 and 16).
The breadth of the amended Claim 1 “the amino acid sequence produced by exons…of a functional vWF gene” allow for one or more mutations. Thus, it is unclear to which vWF gene Claim 5 refers. Similarly, it is unclear to which vWF transgene Claims 10 and 19 refer.
The instant claim(s) as a whole do not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
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.
4. The prior rejection of Claims 1, 7-12, 21, and 24 under AIA 35 U.S.C. 103 as being unpatentable over Ayares et al (WO 2017/044864; of record in IDS) in view of Choi et al (U.S. Patent 8,791,247) and Wang et al (In Vivo Gene Transfer Strategies to Achieve Partial Correction of von Willebrand Disease, Human Gene Therapy 23: 576-588, 2012; of record in IDS) is withdrawn in light of Applicant’s amendments to Claim 1. Further, Applicant argues that the claims require the transgene to be inserted into an intron, a limitation that Ayares et al, Choi et al, and Wang et al do not teach/disclose, which the Examiner finds persuasive.
5. The prior rejection of Claims 1, 14-19, 21, and 24 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Ayares et al (WO 2017/044864; of record in IDS) in view of Choi et al (U.S. Patent 8,791,247) and Wang et al (2012; of record in IDS) is withdrawn in light of Applicant’s amendments to Claim 1. Further, Applicant argues that the claims require the transgene to be inserted into an intron, a limitation that Ayares et al, Choi et al, and Wang et al do not teach/disclose, which the Examiner finds persuasive.
6. The prior rejection of Claims 5, 21, and 24 under AIA 35 U.S.C. 103 as being unpatentable over Ayares et al (WO 2017/044864; of record in IDS) in view of Choi et al (U.S. Patent 8,791,247) and Wang et al (2012; of record in IDS), as applied to Claims 1, 7-12, 14-19, 21, and 24 above, and in further view of Watson et al (WO 2018/112282; priority to at least December 14, 2017; of record) is withdrawn for reasons discussed above.
7. Claims 1, 5, 10, 19, 21, and 24 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Ayares et al (WO 2017/044864; of record in IDS) in view of Choi et al (U.S. Patent 8,791,247; of record), Wang et al (2012; of record in IDS), Chen et al (Engineering Human Stem Cell Lines with Inducible Gene Knockout using CRISPR/Cas9, Cell Stem Cell 17: 233-244, 2015; of record), and GenBank AH005287 (human vWF gene; 2016).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Applicant has amended independent Claim 1 to recite ‘wherein the transgene comprises… encodes the amino acid sequence produced by exons… of a functional vWF gene”, thereby broadening the scope of the first and/or second vWF coding sequence(s).
As discussed in the prior Office Action, the term "comprising" and “encodes” is/are 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).
While it is clear that the claimed first transgene must comprise at least the amino acids of exons 2-22, said first transgene may further comprise the amino acids of exons 1 and/or 23, 24, 26, 28,…, 40, 42, 46, 48, 50, and/or 52.
While it is clear that the claimed second transgene must comprise at least the amino acids of exons 29-52, said second transgene may further comprise the amino acids of exons 2, 4, 6, 8, … 24, 26, and/or 28.
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).
With respect to Claims 1 and 5, Ayares et al is considered relevant prior art for having disclosed a method of editing the endogenous vWF gene of a host cell, the method comprising the step of replacing some or all of the porcine endogenous vWF gene with the equivalent human vWF counterparts (e.g. pg 13, para 1).
Ayares et al disclosed the human vWF transgenes may be integrated into the endogenous porcine vWF gene using the CRISPR/Cas system or TALEN system (e.g. pg 39), whereby the human vWF transgenes are in the form of a cDNA or genomic fragments.
Ayares et al disclosed the transgene encodes exons 22-28 (e.g. pg 39, para 2; Figure 17).
The ordinary artisan immediately recognizes that the partial vWF donor template 5’ homology arm naturally comprise a splice acceptor, and the 3’ homology arm naturally comprises a splice donor, so as to achieve correct expression of the edited vWF gene. Furthermore, Ayares et al disclosed the editing vectors may comprise heterologous splice donor and/or acceptor sequences (e.g. pg 36, para 2, “splice acceptor sequences, splice donor sequences, transcription start sequences, and transcription stop sequences”; pg 37, last para, “insertions can include… artificial splice acceptors….or splice donors”).
This targeting vector also contained both GFP and puromycin-resistance genes to select and enrich for integration of the targeting vector (e.g. pg 9, Figure 12 legend; pg 109, para 1) and thus also comprises a terminator.
Ayares et al do not disclose wherein the transgene encodes:
i) a partial vWF coding sequence encoding at least the amino acids of exons 2-22; or
ii) a partial vWF coding sequence encoding at least the amino acids of exons 29-52.
However, prior to the effective filing date of the instantly claimed invention, Choi et al is considered relevant prior art for having disclosed expression vectors encoding human vWF, wherein the expression vector comprises a promoter, a cDNA encoding at least a portion of human vWF, and a terminator (e.g. Figure 1).
Choi et al disclosed wherein the human vWF transgene encodes:
exons 1-23 (D1, D2, D’, D3);
exons 1-28 (D1, D2, D’, D3, A1);
exons 1-32 (D1, D2, D’, D3, A1, A2); or
exons 1-52 (e.g. Fig 5A; col. 4, lines 25-27; col. 6, lines 1-40).
It is axiomatic that the human vWF transgenes comprise a promoter and a terminator.
Wang et al is considered relevant prior art for having taught a method of restoring expression of wildtype vWF in a cell in vitro, the method comprising:
transducing cells with rAAV8 expression vectors encoding trans-splicing vWF mini-genes,
wherein the 5’ cDNA encodes exons 1-28(partial), and
wherein the 3’ cDNA encodes exons 28(partial)-52 (e.g. Figure 1, legend, AAV8… in vitro),
thereby achieving expression of functional vWF from the trans-splicing molecules (e.g. pg 582, col. 2).
Ayares et al disclosed an example wherein the vWF transgene replaces endogenous exons 22-28 (e.g. Figure 12).
Ayares et al do not disclose wherein the vWF transgene is inserted into a single intron.
However, prior to the effective filing date of the instantly claimed invention, Chen et al is considered relevant prior art for having taught the use of the CRISPR/Cas9 system to generate knock-in transgene expression cassettes within the intron of the artisan’s gene of interest, wherein said knock-in transgene expression cassette comprises a promoter operably linked to the artisan’s transgene of interest to be expressed (e.g. Figures 1A-B, 2A and C, 3A-B).
Chen et al taught that the artisan’s transgene of interest may be inserted into the artisan’s target gene of interest via exon replacement (e.g. Figures 1b, 2a, and 2c), as per Ayares et al, or via intronic insertion (e.g. Figure 3a-b).
GenBank AH005287 is considered relevant prior art for having taught the nucleotide sequence of the human vWF gene, including introns and exons.
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 and methods of gene editing. 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 nucleic acid encoding a partial human vWF cDNA comprising exons 22-28 with a second nucleic acid encoding a partial human vWF cDNA comprising exons 1-23, exons 1-28, exons 1-32, or exons 1-52, in a method of editing an endogenous vWF gene 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 nucleic acid encoding a partial human vWF cDNA comprising exons 22-28 with a second nucleic acid encoding a partial human vWF cDNA comprising exons 1-23, exons 1-28, exons 1-28(partial), exons 1-32, exons 28(partial)-52, or exons 1-52, in a method of editing an endogenous vWF gene because those of ordinary skill in the art previously recognized and successfully reduced to practice the expression of recombinant human vWF polypeptides from vWF transgenes comprising exons 1-23, exons 1-28, exons 1-28(partial), exons 1-32, exons 28(partial)-52, or exons 1-52.
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 method of editing an endogenous vWF gene comprising the step of introducing a vWF transgene into the endogenous vWF gene via exon(s) replacement, as disclosed by Ayares et al, with the step of introducing a vWF transgene into the endogenous vWF gene via intronic insertion, with a reasonable expectation of success because Chen et al taught that the artisan’s transgene of interest may be inserted into the artisan’s target gene of interest via exon replacement (e.g. Figures 1b, 2a, and 2c), as per Ayares et al, or via intronic insertion (e.g. Figure 3a-b), and in light of the prior knowledge of the vWF intron/exon gene structure, the ordinary artisan would know which intron to insert the respective transgene(s).
Independent Claim 1 encompasses, for example, insertion of a transgene encoding exons 2-52 inserted into the vWF intron 1, which is not considered to be materially different than the exon 1-52 construct of Choi et al because the translation start site is in exon 2, and thus the exon 1-52 construct of Choi et al would encode the same amino acid sequence as an exon 2-52 construct.
The "mere existence of differences between the prior art and an invention does not establish the invention's nonobviousness." Dann v. Johnston, 425 U.S. 219, 230, 189 USPQ 257, 261 (1976). The gap between the prior art and the claimed invention may not be "so great as to render the [claim] nonobvious to one reasonably skilled in the art."Id.
It would have been obvious to one of ordinary skill in the art to choose from a finite number of identified, predictable options because “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipate success, it is likely that product not of innovation but of ordinary skill and common sense.”
In light of the known gene structure (e.g. GenBank AH005287), those of ordinary skill in the art would have been able to select the known potential options, including the desired intron of interest, into which a vWF transgene replacement is inserted, said transgene including, but not limited to, splice acceptor sequences and/or splice donor sequences, as per Ayares et al. The number of potential options from which to choose is neither astronomical nor insurmountable, and it would only be routine experimentation to determine which intron would yield functional expression of the thus-introduced vWF transgene.
The "mere existence of differences between the prior art and an invention does not establish the invention's nonobviousness." Dann v. Johnston, 425 U.S. 219, 230, 189 USPQ 257, 261 (1976). The gap between the prior art and the claimed invention may not be "so great as to render the [claim] nonobvious to one reasonably skilled in the art."Id.
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 21, Ayares et al disclosed wherein the genetically modified include hepatocytes, blood precursor cells, hematopoietic cells, adult stem cells, and hematopoietic stem cells (e.g., pg 63, last para; pg 64, para 2).
With respect to Claim 24, Ayares et al disclosed wherein the transgene is introduced into the target host cell via an rAAV vector (e.g. pg 25, last para).
Choi et al disclosed wherein the vector may be a lentiviral vector or an AAV vector (e.g. col. 3, lines 14-16).
With respect to Claims 10 and 19, Ayares et al disclosed the transgene encodes exons 22-28, the 5’ portion of which inserts into intron 21 and the 3’ portion of which inserts into intron 29 (e.g. pg 39, para 2; Figure 17).
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 method of editing an endogenous vWF gene comprising the step of introducing a vWF transgene into the endogenous vWF gene intron 21 and intron 29 via exon(s) replacement, as disclosed by Ayares et al, with the step of introducing a vWF transgene into the endogenous vWF gene via intronic insertion within intron 22 or intron 29 with a reasonable expectation of success because Chen et al taught that the artisan’s transgene of interest may be inserted into the artisan’s target gene of interest via exon replacement (e.g. Figures 1b, 2a, and 2c), as per Ayares et al, or via intronic insertion (e.g. Figure 3a-b).
It would have been obvious to one of ordinary skill in the art to choose from a finite number of identified, predictable options because “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipate success, it is likely that product not of innovation but of ordinary skill and common sense.”
In light of the known gene structure (e.g. GenBank AH005287), those of ordinary skill in the art would have been able to select the known potential options, including the desired intron of interest, into which the artisan’s vWF transgene replacement is inserted, said transgene including, but not limited to, splice acceptor sequences and/or splice donor sequences, as per Ayares et al. The number of potential options from which to choose is neither astronomical nor insurmountable, and it would only be routine experimentation to determine which intron would yield functional expression of the thus-introduced vWF transgene.
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).
The specification fails to disclose an element of criticality for integration of the transgene into intron 22 and/or 29. The ordinary artisans previously recognized the scientific and technical concepts of designing the 5’ and 3’ homology arms to include the artisan’s desired site of integration (e.g. Chen et al, Figure 3a), and Ayares et al successfully demonstrated intron 21 and intron 29 sequences used in the homology arm(s).
The specification fails to disclose an element of criticality for integration of the transgene into intron 20, 21, 22, and/or 23, as opposed to the insertion in intron 21 of the prior art.
The specification fails to disclose an element of criticality for integration of the transgene into intron 28, 29, 32, and/or 34, as opposed to the insertion in intron 28 of the prior art.
The "mere existence of differences between the prior art and an invention does not establish the invention's nonobviousness." Dann v. Johnston, 425 U.S. 219, 230, 189 USPQ 257, 261 (1976). The gap between the prior art and the claimed invention may not be "so great as to render the [claim] nonobvious to one reasonably skilled in the art."Id.
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 cited references do not teach the transgene only encodes exons 2-22 or exons 29-52.
Applicant’s argument(s) has been fully considered, but is not persuasive. The claims do not recite “only encodes exons 2-22 or exons 29-52”. As discussed above, amended independent Claim 1 recites ‘wherein the transgene comprises… encodes the amino acid sequence produced by exons… of a functional vWF gene”, thereby broadening the scope of the first and/or second vWF coding sequence(s).
As discussed in the prior Office Action, the term "comprising" and “encodes” is/are 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).
While it is clear that the claimed first transgene must comprise at least the amino acids of exons 2-22, said first transgene may further comprise the amino acids of exons 1 and/or 23, 24, 26, 28,…, 40, 42, 46, 48, 50, and/or 52.
While it is clear that the claimed second transgene must comprise at least the amino acids of exons 29-52, said second transgene may further comprise the amino acids of exons 2, 4, 6, 8, … 24, 26, and/or 28.
The breadth of the claimed transgenes reasonably encompass embodiments taught/disclosed by Choi et al and/or Wang et al, e.g. exons 1-23, exons 1-28, exons 1-28(partial), exons 1-32, exons 28(partial)-52, or exons 1-52.
Applicant argues that the ordinary artisan would not compare exons of a protein to a mere subset of numbers within a range because each region of the protein has a specific role in the structure and function of the vWF protein.
Applicant’s argument(s) has been fully considered, but is not persuasive. As discussed above, those of ordinary skill in the art previously recognized the vWF gene organization, including introns and exons (e.g. GenBank AH005287), as well as the different functional domains of the vWF protein (see references cited in 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejection).
It would have been obvious to one of ordinary skill in the art to choose from a finite number of identified, predictable options because “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipate success, it is likely that product not of innovation but of ordinary skill and common sense.”
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).
Conclusion
8. No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KEVIN K. HILL whose telephone number is (571)272-8036. The examiner can normally be reached 12pm-8pm EST.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638