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 October 9, 2025.
Election/Restrictions
Applicant has elected without traverse the invention of Group I, claim(s) 12-13, 15-16, and 21, drawn to a vector that comprises a 3' LTR comprising one or more promoter sequences operably linked to a sequence encoding one or more CRISPR guide sequences.
Within Group I, Applicant has elected without traverse the following species, wherein:
i) the alternative structural feature of the vector is the LTR comprises a Hl promoter sequence and/or a U6 promoter sequence, as recited in Claim 13(a); and
ii) the alternative structure encoded by the additional nucleic acid sequence is one or more of the CRISPR guide sequences specific for a locus controlling the expression of the TCR-CD3 complex, as recited in Claim 16(a).
The instant specification discloses that inactivation or disruption of TRAC is an embodiment of “a locus controlling the expression of the TCR-CD3 complex” (e.g pg 22, lines 14-16; pg 39, lines 14-16), as generically recited in Claim 16(a). Thus, the Examiner rejoins species embodiments 16(a) and 16(b) of the alternative structure encoded by the additional nucleic acid sequence.
Amendments
Applicant's response and amendments, filed October 9, 2025, is acknowledged.
Applicant has cancelled Claims 1-11, 14, 16-20, and 22-38, amended Claims 12 and 39, withdrawn Claims 15 and 21, and 40, and added new claims, Claim 41.
Claims 12-13, 15, 21, and 39-41 are pending.
Claims 15, 21, and 40 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 12-13, 39, and 41 are under consideration.
Priority
This application is a 371 of PCT/GB2017/053862 filed on December 21, 2017.
Acknowledgment is made of Applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d). Certified copies of the foreign patent application UK 1706101.1 filed on April 18, 2017 and UK 1621874.5 filed on December 21, 2016 are provided with the instant application.
Claim Rejections - 35 USC § 112
1. The prior rejection of Claims 12-13, 16, and 39-40 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of Applicant’s amendment to Claim 12 cancelling recitation of “TCR beta constant locus”, which the Examiner finds persuasive.
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. Claims 12-13, 39, and 41 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Lee et al (U.S. 2017/0016027; filed July 13, 2016, priority to 62/191,918 filed on July 13, 2015; of record) in view of Duchateau et al (WO 14/191128; of record), Valton et al (available online July 21, 2015; of record), Hoban et al (September 2016; of record), Kotini et al (available online March 23, 2015; of record), and Porteus (available online November 9, 2015; 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 Claim 12, Lee et al is considered relevant prior art for having disclosed editing the genome of a host cell, e.g. a T cell, using CRISPR/Cas system (e.g. [0018]; as also disclosed in ‘918 [0008]) to insert a therapeutic transgene into a first endogenous locus of the host cell’s genome (e.g. [0018]; as also disclosed in ‘918 [0008]), wherein the nuclease targets the PD1 or CTLA-4 gene, and the CAR-encoding sequence integrates into the first endogenous locus ([0036]; as also disclosed in ‘918 [0180]). Alternatively, the CAR transgene may integrate into a safe harbor locus [0014, 28]. Lee et al disclosed wherein a second nuclease may inactivate the TRAC (syn. TCRA) locus (e.g. [0036]; as also disclosed in ‘918 [0140]).
Thus, those of ordinary skill in the art previously recognized the scientific and technical concept whereby a chimeric antigen receptor transgene may be inserted into the PD1 locus, and that the gene editing system is used to also inactivate the TRAC locus, whereby the CRISPR/Cas system may be used to perform the targeted genome editing.
Lee et al disclosed wherein the viral vector used to deliver the transgene may be an AAV vector (comprises inverted terminal repeats (ITRs)) or a lentiviral vector (comprises long terminal repeats (LTRs)) [0016, 187], and illustrated an example a viral vector comprising 5’ and 3’ inverted terminal repeats (ITRs), and a CAR transgene flanked 5’ and 3’ with homology arms to facilitate recombination into the targeted genomic locus (e.g. Figure 1).
Duchateau et al is considered relevant prior art for having disclosed viral vectors comprising a nucleic acid a CRISPR guide RNA (pg 19, lines 1-4), and wherein the CRISPR guide RNA targets TCRalpha (syn. TRAC) (e.g. Table 2), wherein said vector does not encode a Cas DNA modification enzyme, for example, the guide RNA may be transcribed from DNA sequences stably integrated into the host cell genome using retroviral vectors, and the Cas9 is introduced into the cell via electroporation of mRNA. Transient expression of Cas9 from the mRNA resulted in high gene editing transformation rate and was less harmful to the T cells (pg 49, lines 4-9). Duchateau et al disclosed wherein the TRAC (syn. TCRA) immune checkpoint gene may be inactivated in the T cells along with inactivation of PD1 or CTLA-4 (e.g. pg 31, lines 9-11, 19-20, and 24).
While the Duchateu et al working example demonstrates introducing the CAR transgene into the TRAC locus, the invention as a whole is not limited to that embodiment, nor does it criticize, discredit, or otherwise discourage the solution presently claimed. See also claims 1, 26-28, 31-34, and 40 (specifies introduction of a CAR transgene anywhere).
Thus, those of ordinary skill in the art previously recognized the existence of gRNAs specific for the TRAC locus to thereby inactivate the TRAC locus, whereby the CRISPR/Cas system may be used to perform the targeted genome editing.
Valton et al is considered relevant prior art for having taught production of CAR T cells, whereby the lentiviral vector encoding a CAR transgene integrates into a first endogenous locus that is not a TCRA (syn. TRAC) locus, and the TCRA locus is subsequently inactivated using a gene editing system (e.g. Figure 4a-b).
Lee et al do not disclose wherein the viral vector encoding the donor CAR transgene further comprises a promoter operably linked to a CRISPR gRNA.
However, prior to the effective filing date of the instantly claimed invention, Hoban et al is considered relevant prior art for having taught a lentiviral vector comprising:
i) a promoter sequence operably linked to a CRISPR sgRNA (pg 1563, col. 1; Figure 1b, legend; Figure S4, “U6-BC2 gRNA”); and
ii) a therapeutic donor template to correct the host cell’s sickle cell mutation in the beta-globin gene (Title, Abstract),
wherein said vector does not encode a Cas9 DNA modification enzyme.
Hoban et al do not teach wherein the promoter operably linked to the CRISPR gRNA are placed in the 3’ LTR of the lentiviral vector.
However, prior to the effective filing date of the instantly claimed invention, Kotini et al is considered relevant prior art for having taught a lentiviral vector comprising:
i) a 3’ LTR comprising a promoter sequence operably linked to a CRISPR gRNA (“U6-gRNA”); and
ii) a transgene expression cassette encoding GFP,
wherein said vector does not encode a Cas9 DNA modification enzyme (pg 12, Materials and Methods, col. 2, CRISPR Cas9-mediated knockout of EZH2; Supplementary Figure 10a).
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 the design of expression 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.
Porteus is considered relevant prior art for having taught that the CRISPR/Cas9 gene editing system may be used to introduce a therapeutic nucleic acid, wherein the therapeutic nucleic acid may be a donor template encoding a therapeutic correction to a point mutation, a gene correction, or introduction of an exogenous therapeutic gene (Figure 3, “Therapeutic genome editing using Homologous Recombination (HR)”; pg 174, “Functional Gene Correction”, “a wild-type cDNA is targeted by HR to integrate”; pg 175, “therapeutic proteins such as erythropoietin”). Porteus taught the donor vector may be a viral vector, e.g. a lentiviral vector (Figure 3, legend).
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); 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). 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 arrive at a lentiviral vector comprising:
i) a transgene encoding a chimeric antigen receptor; and
ii) a 3’ LTR comprising a promoter operably linked to a CRISPR guide RNA specific for the TRAC locus,
with motivation and a reasonable expectation of success because those of ordinary skill in the art previously recognized the scientific and technical concepts that:
a) host cells, including T cells, can be genome edited using guided nucleases such as the CRISPR/Cas system to express an integrated transgene encoding a chimeric antigen receptor, whereby the chimeric antigen receptor is integrated into a locus other than the TRAC locus, e.g. PD-1 or a safe harbor locus, via the guided nuclease system (Lee et al; Duchateau et al);
b) the CAR T cell may be further modified to inactivate the endogenous TRAC locus (Lee et al, Duchateau et al; Valton et al);
c) the TRAC locus can be inactivated using guided nucleases such as the CRISPR/Cas system in a host cell, including a T cell (Lee et al, Duchateau et al; Valton et al);
d) the donor therapeutic transgene is introduced into the targeted host cell via AAV or lentiviral vectors (Lee et al, Valton et al; Hoban et al, Porteus et al); and
e) the same viral vector may encode both the promoter operably linked to the CRISPR gRNA and the transgene (Hoban et al, Kotini et al), whereby Kotini et al successfully demonstrated expressing the CRISPR sgRNA as an expression cassette located in at least the 3’ LTR of a lentiviral vector (Suppl Figure 10a).
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 combine a transgene encoding a chimeric antigen receptor and a 3’ LTR comprising a promoter operably linked to a CRISPR guide RNA specific for a TRAC locus in a lentiviral vector with a reasonable expectation of success because all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention.
The motivation to combine can arise from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combined for their common known purpose. MPEP §2144.
An artisan would be motivated to combine transgene encoding a chimeric antigen receptor and a 3’ LTR comprising a promoter operably linked to a CRISPR guide RNA specific for a TRAC locus in a lentiviral vector because Lee et al disclosed editing the genome of a host cell, e.g. a T cell, using CRISPR/Cas system to insert a therapeutic transgene into an endogenous locus of the host cell’s genome, whereby the CAR T cell may be further edited with a guided nuclease that targets the TRAC locus (syn. TCRalpha), and Kotini et al successfully demonstrated designing, and using, a lentiviral vector comprising the combination of a transgene of interest and a 3’ LTR comprising a promoter operably linked to a CRISPR guide RNA specific for the artisan’s locus of interest (Suppl Figure 10a). The combination of elements provides the targeting gRNA nucleic acid and the desired donor chimeric antigen receptor transgene into a single vector, whereby Hoban et al had successfully demonstrated the combination of the CRISPR gRNA and therapeutic nucleic acid in a single lentiviral vector for genome editing and correction of a genetic mutation (Title). The ordinary artisan could have combined the elements as claimed by known methods and that in combination, each element merely would have performed the same function as it did separately, and the ordinary artisan would have recognized that the results of the combination were predictable.
It is well known that it is prima facie obvious to combine two or more ingredients each of which is taught by the prior art to be useful for the same purpose in order to form a third composition which is useful for the same purpose (as well as to use such a composition for that purpose - i.e., genome editing to knockout or inactivate an endogenous gene in the host cell, as well as genome editing to introduce the artisan’s desired therapeutic transgene, i.e. chimeric antigen receptor, into a targeted location of the host cell’s genome). The idea for combining them flows logically from their having been used individually in the prior art, and from them being recognized in the prior art as useful for the same purpose. This rejection is based on the well-established proposition of patent law that no invention resides in combining old ingredients of known properties where the results obtained thereby are no more than the additive effect of the ingredients. In re Kerkhoven, 626 F.2d 846, 850, 205 U.S.P.Q. 1069 (CCpA 1980), In re Sussman, 1943 C.D. 518; In re Pinten, 459 F.2d 1053, 173 USPQ 801 (CCPA 1972); In re Susi, 58 CCPA 1074, 1079-80; 440 F.2d 442, 445; 169 USPQ 423,426 (1971); In re Crockett, 47 CCPA 1018, 1020-21; 279 F.2d 274, 276-277; 126 USPQ 186, 188 (1960).
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 13, Kotini et al taught a U6 promoter operably linked to the guide RNA (e.g. Supplementary Figure 10a).
Hoban et al taught a U6 promoter operably linked to the guide RNA (e.g. Supplementary Figure S4).
Duchateau et al disclosed a U6 promoter operably linked to the guide RNA (e.g. pg 5, lines 16-17, “sgRNA specific for TRAC genes under the control of U6 promoter”; pg 57, claim 22).
With respect to Claims 39 and 41, Lee et al disclosed wherein the viral vector used to deliver the transgene may be an AAV vector (comprises inverted terminal repeats (ITRs)) or a lentiviral vector (comprises long terminal repeats (LTRs)) [0016, 187].
Duchateau et al disclosed the vector may be a viral vector, e.g. lentiviral vector (e.g. pg 19, lines 1-7; pg 20, lines 18-19).
Valton et al taught the use of a lentiviral vector encoding the CAR transgene.
Kotini et al taught the use of lentiviral vectors (e.g. Supplementary Figure 10a).
Hoban et al taught the use of lentiviral vectors (e.g. Supplementary Figure S4).
Porteus taught the use of a viral vector (e.g. Figure 3).
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, absent evidence to the contrary, the invention as a whole is prima facie obvious.
Response to Arguments
Applicant argues that Valon et al used TALENs to edit the TRAC site, not CRISPR/Cas system, and used a lentiviral vector to deliver the CAR transgene.
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).
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.<
While the Duchateu et al working example demonstrates introducing the CAR transgene into the TRAC locus, the invention as a whole is not limited to that embodiment, nor does it criticize, discredit, or otherwise discourage the solution presently claimed. See also claims 1, 26-28, 31-34, and 40 (specifies introduction of a CAR transgene anywhere).
Thus, those of ordinary skill in the art previously recognized the existence of gRNAs specific for the TRAC locus to thereby inactivate the TRAC locus, whereby the CRISPR/Cas system may be used to perform the targeted genome editing.
Valton et al is considered relevant prior art for having taught production of CAR T cells, whereby the lentiviral vector encoding a CAR transgene integrates into a first endogenous locus that is not a TCRA (syn. TRAC) locus, and the TCRA locus is subsequently inactivated using a gene editing system (e.g. Figure 4a-b).
Lee et al disclosed editing the genome of a host cell, e.g. a T cell, using CRISPR/Cas system (e.g. [0018]; as also disclosed in ‘918 [0008]) to insert a therapeutic transgene into a first endogenous locus of the host cell’s genome (e.g. [0018]; as also disclosed in ‘918 [0008]), wherein the nuclease targets the PD1 or CTLA-4 gene, and the CAR-encoding sequence integrates into the first endogenous locus ([0036]; as also disclosed in ‘918 [0180]). Alternatively, the CAR transgene may integrate into a safe harbor locus [0014, 28].
Lee et al disclosed wherein a second nuclease may inactivate the TRAC (syn. TCRA) locus (e.g. [0036]; as also disclosed in ‘918 [0140]).
Thus, those of ordinary skill in the art previously recognized the scientific and technical concept whereby a chimeric antigen receptor transgene may be inserted into the PD1 locus, and that the gene editing system is used to also inactivate the TRAC locus, whereby the CRISPR/Cas system may be used to perform the targeted genome editing.
Applicant argues that the claimed vector delivers both the CAR transgene and a sgRNA for CRISPR editing, thereby linking editing to CAR expression.
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).
Lee et al disclosed wherein the viral vector used to deliver the transgene may be an AAV vector (comprises inverted terminal repeats (ITRs)) or a lentiviral vector (comprises long terminal repeats (LTRs)) [0016, 187], and illustrated an example a viral vector comprising 5’ and 3’ inverted terminal repeats (ITRs), and a CAR transgene flanked 5’ and 3’ with homology arms to facilitate recombination into the targeted genomic locus (e.g. Figure 1).
Hoban et al is considered relevant prior art for having taught a lentiviral vector comprising:
i) a promoter sequence operably linked to a CRISPR sgRNA (pg 1563, col. 1; Figure 1b, legend; Figure S4, “U6-BC2 gRNA”); and
ii) a therapeutic donor template to correct the host cell’s sickle cell mutation in the beta-globin gene (Title, Abstract),
wherein said vector does not encode a Cas9 DNA modification enzyme.
Kotini et al is considered relevant prior art for having taught a lentiviral vector comprising:
i) a 3’ LTR comprising a promoter sequence operably linked to a CRISPR gRNA (“U6-gRNA”); and
ii) a transgene expression cassette encoding GFP,
wherein said vector does not encode a Cas9 DNA modification enzyme (pg 12, Materials and Methods, col. 2, CRISPR Cas9-mediated knockout of EZH2; Supplementary Figure 10a).
Thus, prior to the effective filing date of the instantly claimed invention, those of ordinary skill in the art previously recognized the scientific and technical concepts of designing a single vector to deliver both the artisan’s transgene of interest and a sgRNA for CRISPR editing, thereby linking editing to expression of the artisan’s transgene of interest.
Lee et al is considered relevant prior art for having disclosed editing the genome of a host cell, e.g. a T cell, using CRISPR/Cas system (e.g. [0018]; as also disclosed in ‘918 [0008]) to insert a therapeutic transgene into a first endogenous locus of the host cell’s genome (e.g. [0018]; as also disclosed in ‘918 [0008]), wherein the nuclease targets the PD1 or CTLA-4 gene, and the CAR-encoding sequence integrates into the first endogenous locus ([0036]; as also disclosed in ‘918 [0180]). Alternatively, the CAR transgene may integrate into a safe harbor locus [0014, 28]. Lee et al disclosed wherein a second nuclease may inactivate the TRAC (syn. TCRA) locus (e.g. [0036]; as also disclosed in ‘918 [0140]).
Thus, those of ordinary skill in the art previously recognized the scientific and technical concept whereby a chimeric antigen receptor transgene may be inserted into the PD1 locus, and that the gene editing system is used to also inactivate the TRAC locus, whereby the CRISPR/Cas system may be used to perform the targeted genome editing.
Applicant argues that the claimed lentiviral system delivers both CRISPR/Cas9 elements and the CAR, and the resulting TRAC-Knockout allows enrichment of cells to a high degree of purity for coupled CAR expression.
Applicant’s argument(s) has been fully considered, but is not persuasive.
As a first matter, instant claims are directed to a Product vector, not a Method of Making.
As a second matter, instantly claimed vector recites that it does not encode Cas9 enzyme in said vector, and thus, contrary to Applicant’s argument, does not deliver CRISPR/Cas9 elements.
Applicant argues that Lee et al teach away from the instantly claimed invention because the working example introduces the CAR transgene into the TRAC locus.
Applicant’s argument(s) has been fully considered, but is not persuasive. A prior art reference that "teaches away" from the claimed invention is a significant factor to be considered in determining obviousness; however, "the nature of the teaching is highly relevant and must be weighed in substance. "The prior art's mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).
While the Lee et al working example demonstrates introducing the CAR transgene into the TRAC locus, the invention as a whole is not limited to that embodiment, nor does it criticize, discredit, or otherwise discourage the solution presently claimed. Rather, Lee et al disclosed editing the genome of a host cell, e.g. a T cell, using CRISPR/Cas system (e.g. [0018]; as also disclosed in ‘918 [0008]) to insert a therapeutic transgene into a first endogenous locus of the host cell’s genome (e.g. [0018]; as also disclosed in ‘918 [0008]), wherein the nuclease targets the PD1 or CTLA-4 gene, and the CAR-encoding sequence integrates into the first endogenous locus ([0036]; as also disclosed in ‘918 [0180]). Alternatively, the CAR transgene may integrate into a safe harbor locus [0014, 28].
Lee et al disclosed wherein a second nuclease may inactivate the TRAC (syn. TCRA) locus (e.g. [0036]; as also disclosed in ‘918 [0140]).
Thus, those of ordinary skill in the art previously recognized the scientific and technical concept whereby a chimeric antigen receptor transgene may be inserted into the PD1 locus, and that the gene editing system is used to also inactivate the TRAC locus, whereby the CRISPR/Cas system may be used to perform the targeted genome editing.
Citation of Relevant Prior Art
3. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Maruyama et al (Increasing the efficiency of precise genome editing with CRISPR-Cas9 by inhibition of nonhomologous end joining, Nature Biotechnology 33(5): 538-542, May 2015; of record) is considered relevant prior art for having taught a lentiviral vector encoding a sgRNA, but does not encode a CAS enzyme, and a host cell whose genome comprises said lentiviral vector. Maruyama et al taught wherein said host cell further comprises a second vector encoding an inducible Cas9 (e.g. pg 539, col. 2; Online Methods, Lentivirus transduction…. sgRNA stable Cas9-inducible cells; Online Methods, HDR-mediated targeting, lentivirus carrying sgRNA-encoding DNA).
Thus, those of ordinary skill in the art previously recognized the scientific and technical concepts of separating the sgRNA expression vector from the Cas9-encoding nucleic acid, and that the Cas9 enzymatic activity is elicited in the target host cell at a time after stable expression of the sgRNA to thereby induce the targeted genome edit(s).
Askou et al (Multigenic lentiviral vectors for combined and tissue-specific expression of miRNA- and protein-based antiangiogenic factors, Molecular Therapy—Methods & Clinical Development, vol. 2: e14064; doi:10.1038/mtm.2014.64; 11 pages, available online January 28, 2015; of record) is considered relevant prior art for having taught a lentiviral vector expressing microRNAs and a transgene, wherein the transgene is a marker protein (AsRED) or a therapeutic protein (PEDF) (Figure 1a, legend; pg 5, col. 2, “The AsRED gene was replaced with the PEDF gene and expression of Pigment Epithelium-Derived Factor (PEDF) from the multigenic LV vectors was assessed”). Askou et al taught that transduction with the multigenic lentiviral vector “resulted in robust miRNA-directed downregulation of VEGF expression and, in parallel, overexpression of PEDF” (pg 7, col. 1).
Askou et al taught and successfully demonstrated the ability to substitute an expression cassette encoding a marker gene for an expression cassette encoding a therapeutic protein (pg 5, col. 2, “The AsRED gene was replaced with the PEDF gene and expression of Pigment Epithelium-Derived Factor (PEDF) from the multigenic LV vectors was assessed”).
Yu et al (The Cytotoxic Effect of RNA-Guided Endonuclease Cas9 on Human Hematopoietic Stem and Progenitor Cells (HSPCs), Molecular Therapy 24(Suppl 1): Abstract 564, pg S225-226; May, 2016; of record) is considered relevant prior art for having taught a lentiviral vector comprising an sgRNA expression cassette, said vector further comprising an expression cassette comprising a heterologous protein (GFP) and said vector does not encode Cas9 or a Cas9 expression cassette (pg S225, col. 2; Figure 1b).
Yu et al taught that sustained expression of Cas9 in human hematopoietic stem and progenitor cells (HSPCs) has significant toxicity, and that an alternative Cas9 delivery method for HSPCs is required. Yu et al taught the transfection of Cas9 mRNA (pg S225, col. 2) yielded superior results than when using a lentiviral vector comprising the sgRNA expression cassette, the expression cassette comprising a heterologous protein (GFP) and the Cas9 expression cassette (Figure 2; compare B vs D).
Conclusion
4. 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.
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