DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 September 10, 2026 has been entered.
Applicants previously canceled claims 1-195 and 215. Claim 214 remains withdrawn from further consideration as being drawn to a nonelected invention. Applicants amend withdrawn claim 214. Claims 196-213 and 216 are under examination.
Any objection or rejection of record in the previous Office Action, mailed July 8, 2026, which is not addressed in this action has been withdrawn in light of Applicants’ amendments and/or arguments.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 196-208 are rejected under 35 U.S.C. 103 as being unpatentable over Urnov et al. (PCT Patent Application Publication No. WO 2019/204643, published October 24, 2019, filed April 18, 2019, and claiming priority to U.S. Provisional Patent Application Nos. 62/819,237; 62/738,825; 62/716,223; 62/690,905; and 62/659,656; filed March 15, 2019; September 28, 2018; August 8, 2018; June 27, 2018; and April 18, 2018, respectively, and cited in the Information Disclosure Statement filed August 29, 2022) in view of Agrawal et al. (U.S. Patent No. 9,828,601) and Bonas et al. (PCT Patent Application Publication No. WO 2012/104729, published August 9, 2012, and cited in the Information Disclosure Statement filed March 27, 2024). This rejection is modified as necessitated by Applicants’ amendments.
Regarding claims 196 and 201, Urnov discloses polypeptides and nucleic acid encoding the polypeptides that include a DNA binding domain, and which include repeating units derived from repeat units in proteins from animal pathogens (abstract). Urnov discloses that the repeating units each bind to a single nucleotide or base pair (paragraph [0005]). Urnov discloses the formula for the repeating units , with X1-11 being 11 contiguous amino acids, X12-33, 34, 35, being 20, 21, or 22 contiguous amino acids, and X12-X13 being HK, HD, HA, HN, HG, NN, NG, RN, HI, HV, RT, SN, HS, GS, or LN (paragraphs [0005]-[0013]).
Regarding claim 203 and 206, Urnov discloses that the nucleic acid binding domain can be a modular animal pathogen derived nucleic acid binding domain (MAP-NBD) and indicates that the plurality of repeat units can be rearranged/replaced with other repeat units and cab be arranged in an order such that the nucleic acid binding domain binds to the target nucleic acid (paragraph [0047]). Urnov discloses that any repeat unit in a modular nucleic acid binding domain can be switched with a different repeat unit (paragraph [0047]). Urnov discloses that the modularity can provide for swapping out a repeat unit for another repeat unit to increase affinity for a particular target nucleic acid, allowing for precise targeting of any nucleic acid sequence of interest (paragraph [0047]).
Urnov fails to disclose that the transcription repressor codes for TIM-3 or PD-1/PDCD1. Urnov fails to explicitly disclose the ordering of the repeat units or the location of the target sequence to which the repeat units bind.
Regarding claim 196, Agrawal discloses chimeric transcription repressors specific for the immune checkpoint molecule TIM-3 (abstract and column 10, lines 47-54). Agrawal discloses a TIM-3 specific sequence having the sequence of SEQ ID NO: 41 (Appendix I, SEQ ID NO: 396).
Regarding claim 197, Agrawal further discloses a TIM-3 specific sequence that comprises the sequence of SEQ ID NO: 42 (Appendix I, SEQ ID NO: 396).
Regarding claim 198, Agrawal further discloses a TIM-3 specific gRNA that comprises the sequence of SEQ ID NO: 43 (Appendix I, SEQ ID NO: 396).
Regarding claim 199, Agrawal further discloses a TIM-3 specific gRNA that comprises the sequence of SEQ ID NO: 44 (Appendix I, SEQ ID NO: 396).
Regarding claim 200, Agrawal further discloses a TIM-3 specific gRNA that comprises the sequence of SEQ ID NO: 45 (Appendix I, SEQ ID NO: 396).
Regarding claim 201, Agrawal discloses the transcriptional repression of PD-1 (PDCD1) (abstract and column 10, lines 14-21). Agrawal discloses that the inhibitors may be chimeric transcriptional repressors that comprise a DNA-binding domain (abstract and column 10, lines 14-21). Agrawal discloses a binding sequence that is SEQ ID NO: 1 (Appendix II, SEQ ID NO: 388).
Regarding claim 202, Agrawal discloses a binding sequence that is SEQ ID NO: 1, which comprises SEQ ID NO: 2 (Appendix II, SEQ ID NO: 388).
Regarding claim 204, Agrawal discloses a binding sequence that is SEQ ID NO: 1, which comprises SEQ ID NO: 3 (Appendix II, SEQ ID NO: 388).
Regarding claim 205, Agrawal discloses a binding sequence that is SEQ ID NO: 1, which comprises SEQ ID NO: 4 (Appendix II, SEQ ID NO: 388).
Regarding claim 207, Agrawal discloses a binding sequence that is SEQ ID NO: 1, which comprises SEQ ID NO: 5 (Appendix II, SEQ ID NO: 388)
Regarding claim 208, Agrawal discloses a binding sequence that is SEQ ID NO: 1, which comprises SEQ ID NO: 6 (Appendix II, SEQ ID NO: 388).
Bonas discloses DNA binding domains based upon a TALE and how to design such binding domains (page 19, line 23 to page 20, line2).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to substitute Agrawal’s transcriptional repressor domains of TIM-3 and PD-1/PDCD1 and including the DNA binding domains having the repeat domains of Urnov in order to provide a nucleic acid that encodes a polypeptide comprising a DNA-binding domain, which can be prepared according to the disclosure of Bonas. One of ordinary skill in the art would have been motivated to provide the nucleic acid according to Urnov in view of Agrawal and Bonas in order to control expression and/or repression of a variety of genes in a subject, and which can be used in therapeutic applications based on conditions related to expression and/or repression of genes TIM-3 and PD1/PDCD1 of Agrawal in combination with the DNA binding domains having the repeat units of Urnov.
It would also have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to employ the modularity of Urnov’s repeat units to arrive at the specific ordering of the repeat units, including the location that the repeat unit binds to, using Agrawal’s binding sequences for PD1/PDCD1 because, as disclosed by Urnov, the repeat units can be arranged in whatever order is desired in order to more effectively target a particular nucleic acid sequence, including those disclosed by Agrawal. One of ordinary skill in the art would have been motivated to arrange the repeat units in the claimed order because this provides for a more efficient and effective targeting of a specific nucleic acid sequence.
Claims 209-213 and 216 are rejected under 35 U.S.C. 103 as being unpatentable over Urnov et al. (PCT Patent Application Publication No. WO 2019/204643, published October 24, 2019, filed April 18, 2019, and claiming priority to U.S. Provisional Patent Application Nos. 62/819,237; 62/738,825; 62/716,223; 62/690,905; and 62/659,656; filed March 15, 2019; September 28, 2018; August 8, 2018; June 27, 2018; and April 18, 2018, respectively, and cited in the Information Disclosure Statement filed August 29, 2022) in view of Triebel et al. (171 Journal of Experimental Medicine 1393-1405 (1990), Kuchroo et al. (PCT Patent Application Publication No. WO 2017/069958, published April 27, 2017, and cited in the Information Disclosure Statement filed March 27, 2024) and Bonas et al. (PCT Patent Application Publication No. WO 2012/104729, published August 9, 2012, and cited in the Information Disclosure Statement filed March 27, 2024). This rejection is modified as necessitated by Applicants’ amendments.
Regarding claim 209, Urnov discloses polypeptides and nucleic acid encoding the polypeptides that include a DNA binding domain, and which include repeating units derived from repeat units in proteins from animal pathogens (abstract). Urnov discloses that the repeating units each bind to a single nucleotide or base pair (paragraph [0005]). Urnov discloses the formula for the repeating units , with X1-11 being 11 contiguous amino acids, X12-33, 34, 35, being 20, 21, or 22 contiguous amino acids, and X12-X13 being HK, HD, HA, HN, HG, NN, NG, RN, HI, HV, RT, SN, HS, GS, or LN (paragraphs [0005]-[0013]).
Regarding claim 213, Urnov discloses a cell that can be a target cell (paragraphs [0160]-[0166]).
Regarding claim 216, Urnov discloses that the number of repeat units can be between 1 and 50 (paragraph [0075]).
Urnov fails to disclose that the transcription repressor codes for LAG-3. Urnov fails to explicitly disclose the ordering of the repeat units or the location of the target sequence to which the repeat units bind.
Regarding claim 209, Triebel discloses the sequence of LAG-3, which includes the sequence of SEQ ID NO: 57 (Figure 1) (Appendix III).
Regarding claim 210, Triebel discloses the sequence of LAG-3, which includes the sequence of SEQ ID NO: 58 (Figure 1) (Appendix III).
Regarding claim 211, Triebel discloses the sequence of LAG-3, which includes the sequence of SEQ ID NO: 59 (Figure 1) (Appendix III).
Regarding claim 212, Triebel discloses the sequence of LAG-3, which includes the sequence of SEQ ID NO: 60 (Figure 1) (Appendix III).
Kuchroo discloses inhibitors of the immune checkpoint molecule LAG-3 (page 8, paragraph [0041]). Kuchroo discloses that the inhibitors may be chimeric transcriptional repressors that comprise a DNA-binding domain based on a TALE (page 17, paragraphs [0107] and [0284]-[0288] and Table 1).
Bonas discloses DNA binding domains based upon a TALE and how to design such binding domains (page 19, line 23 to page 20, line2).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to substitute Triebel’s and Kuchroo’s transcriptional repressor domains of LAG-3 and including the DNA binding domains having the repeat domains of Urnov in order to provide a nucleic acid that encodes a polypeptide comprising a DNA-binding domain, which can be prepared according to the disclosure of Bonas. One of ordinary skill in the art would have been motivated to provide the nucleic acid according to Urnov in view of Triebel, Kuchroo, and Bonas in order to control expression and/or repression of a variety of genes in a subject, and which can be used in therapeutic applications based on conditions related to expression and/or repression of genes LAG-3 of Triebel and Kuchroo in combination with the DNA binding domains having the repeat units of Urnov.
Response to Amendments and Arguments
Regarding the rejections under 35 U.S.C. § 103 Applicants’ arguments have been fully considered, but are not deemed to be persuasive.
Regarding the rejection of claims 196-208, Applicants assert that Agarwal does not recite transcriptional repressors, but instead recites translational repressors, and that Agarwal’s antisense oligonucleotides “supposedly” repress translation, rather than transcription. Applicants assert that Agarwal’s teaching of antisense-mediated gene silencing does not predict a site for DBD-mediated transcriptional repression. Applicants assert that Agarwal does not provide any specific guidance to SEQ ID NO: 41 and that any stretch of at least 12 contiguous nucleotides in the 2,448 nucleobase long TIM-3 sequence can be targeted, and thus not “obvious to try.” Applicants’ assert that neither Urnov nor Bonas remedies the alleged deficiency of Agarwal. Applicants further assert that there is no reasonable expectation of success in combining Urnov, Agarwal, and Bonas.
To begin, it is again noted that the rejection is based upon Urnov in view of Agarwal and Bonas. Regarding Applicants’ arguments relating to Agarwal, it is noted that Agarwal teaches not only translational repression, but also transcriptional repression, as discussed above and previously. Specifically, Agarwal states that the phrase “target nucleic acid,” “refer[s] to a nucleic acid capable of being targeted by gene silencing compounds” (column 9, lines 7-9). Agarwal further recites that “gene expression . . . may involve transcription, RNA splicing, translation, and post-translational modification of a protein.” While Applicants assert that the gene silencing does not predict a DBD-mediated transcription repression site, taken together, these recitations provide for gene silencing by targeting transcription, which would naturally include a transcriptional repressor domain, as required by the claims. As noted above, and previously, Applicants have still not pointed to any specific disclosure in Agarwal that provides that Applicants are correct in that Agarwal only discloses translational repression. Because Agarwal clearly discloses that transcriptional repression results in gene silencing, Applicants’ arguments are still not deemed to be persuasive.
Regarding Applicants re-assertion that Agarwal does not disclose instantly claimed SEQ ID NO: 41, it is noted that while TIM-3 is 2,448 nucleobases long, SEQ ID NO: 41 is 44 nucleobases long. And since the sequence of TIM-3 is known, one of ordinary skill in the art would be able to create a finite number of 44 nucleobase sequences that target any portion of the TIM-3 gene. At the very least, Agarwals’s disclosure provide sufficient information and sequences such that one of ordinary skill in the art would have been able to determine any number of sequences that would bind to TIM-3 and repress transcription. Thus, one of ordinary skill in the art, having the sequence of TIM-3 in front of them, would find it at least obvious to try any of the finite number of 44 nucleobase sequences, including instantly claimed SEQ ID NO: 41. Thus, given Agarwals’s disclosure of the TIM-3 gene and methods of targeting the gene for silencing, one of ordinary skill in the art would have found it, at the very least, obvious to try with a predictable and reasonable expectation of success. See KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398 (2007). Indeed, one of ordinary skill in the art could envision all the species within the genus disclosed by Agarwal. While the number of potential 44-base nucleotides can be considered a high number, it is still predictable to “walk” along the TIM-3 gene and determine each potential 44 base sequence, including instantly claimed SEQ ID NO: 41. Because the nucleic acid is so well-defined, the skilled worker would readily recognize that Agarwal’s 44 base nucleotide sequence is one of many that can be easily predicted, as if each of the different sequences was written out. While determining each of the potential sequences might be impractical, the rejection is one of obviousness. Since TIM-3 is well-defined, one of ordinary skill in the art could have envisioned each of the 2,448 potential sequences.
In addition, not only have Applicants’ not pointed to any particular disclosure of Agarwal regarding only translational repression, rather than transcriptional repression and other methods of gene silencing, Applicants have not provided any objective, factually supported evidence showing that Agarwal relates only to translational repression of TIM-3. Applicants have again provided only arguments of counsel, and arguments of counsel cannot take the place of factually supported objective evidence. See, e.g., In re Huang, 100 F.3d 135,139-40, 40 USPQ2d 1685, 1689 (Fed. Cir. 1996); In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984).
It is noted that Urnov and Bonas are cited for disclosing DNA binding domains and repeat units and DNA binding domains based on TALEs, rather than the disclosure of Agarwal. However, Urnov taken together and as a whole with Agarwal and Bonas still would have led one of ordinary skill in the art directly to the claimed invention.
Regarding the rejections of claim 209-213, Applicants present similar arguments to the rejection of claims 196-208 above, and assert that the cited prior art references do not teach or suggest targeting a sequence present within SEQ ID NO: 57 with a recombinant polypeptide comprising a DNA binding domain and a transcriptional repressor domain, and that there is no disclosure or suggestion of targeting a particular sequence within the LAG-3 gene.
However, as discussed previously and above, one of ordinary skill in the art, having the sequence of LAG-3 in front of them, would find it at least obvious to try any of the finite number of 46 nucleobase sequences, including instantly claimed SEQ ID NO: 57. Thus, given Triebel’s disclosure of the LAG-3 gene and methods of targeting the gene for silencing, one of ordinary skill in the art would have found it, at the very least, obvious to try with a predictable and reasonable expectation of success. See KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398 (2007). Further, Kuchroo definitively discloses transcriptional repressor domains.
For all these reasons, and those cited above, Urnov in view of Agarwal or Triebel and Kuchroo and Bonas is still deemed to render the instant invention obvious.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NANCY J LEITH whose telephone number is (313)446-4874. The examiner can normally be reached Monday - Thursday 8:00 AM - 6:30 PM.
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NANCY J. LEITH
Primary Examiner
Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636
