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
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 June 30, 2025, has been entered.
The amendment filed June 30, 2025, is acknowledged and has been entered. Claims 75-78 have been canceled.
Claims 64 and 67-74 are pending. Claims 64 and 67-74 are under consideration. The elected species are SEQ ID NO: 25 as a species of CD28 transmembrane domain, SEQ ID NO: 40 as a species of CD3zeta signal transduction domain and SEQ ID NO: 29 as a species of iCasp protein.
Grounds of Rejection Maintained
Claim Rejections - 35 USC § 103
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 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.
Claims 64 and 73-74 are rejected under 35 U.S.C. 103 as being unpatentable over Cooper et al (WO 2013/074916 A1, IDS), Hoyos et al (Leukemia, 24, 1160-1170, 2010, of record) and Bertschinger et al (WO 2010/095031 A2, of record).
Cooper et al disclose a monospecific CAR comprising an scFv that binds CD19, a CD28 transmembrane domain, and a cytoplasmic domain of 4-1BB (CD137), CD27 and CD3zeta domain and an inducible caspase 9 domain and wherein the CAR is comprised in a T cell and in a composition comprising such T cells (see entire document, e.g., abstract, pages 2, 4-6, 12, 17 19 and 47, Figures and examples).
Hoyos et al disclose monospecific CAR comprising an scFv that binds CD19, and an inducible caspase 9 domain and wherein the CAR is comprised in a T cell and in a composition comprising such T cells (see entire document, e.g., abstract, pages 1160, 1161, 1165 and 1168 and figures).
Bertschinger et al teach an antibody comprising the instant SEQ ID Nos: 11 and 12 that binds CD19 (see entire document, e.g., abstract and see sequences 1, 2 and 69).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to make a monospecific CAR comprising an scFv that binds CD19, a CD28 transmembrane domain, and a cytoplasmic domain of 4-1BB (CD137), CD27 and CD3zeta domain and an inducible caspase 9 domain and wherein the CAR is comprised in a T cell and in a composition comprising such T cells, since T cells expressing inducible caspase 9 gene have an advantage that allows for induction of apoptosis in the T cells expressing the CAR to provide safety (see Hoyos et al, Pg. 1168, right column) and use the antibody of Bertschinger et al in the CAR constructs suggested above because each component of the CAR has been taught to be a domain that can be used in a CAR or to provide a safety switch to eliminate the T cells expressing the CAR, so such constructs would be considered to be combining prior art elements according to known methods to yield predictable results. Furthermore, one of skill in the art would recognize that the CD19 antibody of Bertschinger et al could be used in making CAR constructs, so using the Bertschinger et al antibody would be considered to be combining prior art elements according to known methods to yield predictable results.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
In the response, Applicant traverses the rejection and argues that:
“Based on the disclosure of Bertschinger, a person of ordinary skill in the art would not have had a reason to use the naive anti-CD19 antibody FM63 of Bertschinger in a CAR because Bertschinger discloses that humanization of the naive anti-CD19 antibody FM63 is necessary to achieve anti-CD19 antibodies with superior binding properties that are able to effectively induce cell death. MPEP 2143.01(VI) provides that "[i]f the proposed modification or combination of the prior art would change the principle of operation of the prior art invention being modified, then the teachings of the references are not sufficient to render the claims prima facie obvious." Thus, a person of ordinary skill in the art would not have had a reason to combine the disclosures of Cooper, Hoyos, and Bertschinger to arrive at the claimed invention.
Even if the skilled person were motivated to use the naive anti-CD19 antibody FM63 of Bertschinger, which the Applicant does not concede, the combination of references would not have led the skilled person to predict that the claimed CARs could display high target killing activities.
MPEP § 716.02(a) explains the test for non-obviousness in view of unexpected results:
"[e]vidence of unobvious or unexpected advantageous properties, such as superiority in a property the claimed compound shares with the prior art, can rebut prima facie obviousness. "Evidence that a compound is unexpectedly superior in one of a spectrum of common properties ... can be enough to rebut a prima facie case of obviousness." No set number of examples of superiority is required." For example, Bertschinger discloses that matured anti-CD19 antibodies induced cell death, while the parental chimeric, the naive anti-CD19 antibody FM63 (comprising a heavy chain and light chain corresponding to SEQ ID NOs: 11 and 12, respectively), had no effect on apoptosis (see, page 86 and FIG. 6 of Bertschinger). Based on this disclosure in Bertschinger, the skilled person would expect that a CAR comprising the naive anti-CD19 antibody FM63 would not have any effect on apoptosis. Surprisingly, CARs of the pending claims displayed high target killing activities (see, e.g., paras. [0293]-[0294] and FIGs. 22-24G of the instant Application). The combination of cited references do not provide the skilled person a reason to expect that the claimed CARs could display high target killing activities."
In response, these arguments are not found persuasive because Cooper and Hoyos both disclose chimeric antigen receptors that target the antigen CD19 which can be used to cause death of cells that express CD19 and chimeric antigen receptors mediate cell death by a different mechanism of action than the antibodies of Bertschinger. Therefore, the cell death results of Bertschinger cannot be extrapolated to chimeric antigen receptors. Here, the binding domain of the anti-CD19 antibody FMC63 used in a CAR and expressed by T cells would be expected to target T cells to CD19 positive cells and then these T cells would be cytotoxic to said CD19 positive cells.
MPEP 2143.01(I) provides that "[t]he disclosure of desirable alternatives does not necessarily negate a suggestion for modifying the prior art to arrive at the claimed invention" so that even if the humanized binding domains were more desirable in this case, using the original FMC63 binding domain would also be considered obvious because known CD19 binding domains can be used in a CAR and one of skill in the art would be motivated to compare CARs comprising the original binding domain to the humanized versions to identify how CARs comprising the original binding domain differ from the humanized version.
Then to address Applicant's argument that the CARs of the pending claims displayed unexpectedly high target killing activities because the naive anti-CD19 antibody FMC63 had no effect on apoptosis, it is again noted that chimeric antigen receptors mediate cell death by a different mechanism of action than antibodies so the results of the cell killing activities of the naive anti-CD19 antibody FMC63 are insufficient to establish that the CARs of the pending claims display unexpectedly high target killing activities. To further address this argument, it is noted that the naive anti-CD19 antibody FMC63 binding domain had been used in the prior art CAR of Jensen (US 2012/0301447 A1, of record) (see page 6) and had been used in a CAR in the prior art of Kochenderfer et al (J Immunother. 2009 September; 32(7):689-702, pages 1-26, of record) (see page 3), so it is evident that the prior art expected the naive anti-CD19 antibody FMC63 binding domain could be used in functional CAR constructs.
Accordingly, after careful and complete consideration of Applicant’s response and the record as a whole, this rejection is being maintained.
Claims 67, 69 and 72 are rejected under 35 U.S.C. 103(a) as being unpatentable over Cooper et al (WO 2013/074916 A1, IDS), Hoyos et al (Leukemia, 24, 1160-1170, 2010, of record) and Bertschinger et al (WO 2010/095031 A2, of record), as applied to claims 64 and 73-74 above, in further view of Chang et al (WO 2015/179801 A1, of record).
The previous combination teaches and suggests that which is set forth in the above 103 rejection.
Chang et al teach a using a chimeric antigen receptor (CAR) composition related CD28 region in CARs comprising the instant SEQ ID NO:25 (see entire document, e.g., abstract and see SEQ 13), a CD27 region comprising the instant SEQ ID NO:38 (see entire document, e.g., abstract and see SEQ 16) and an FKBP sequence comprising the instant SEQ ID NO:30 (see entire document, e.g., abstract and see SEQ 29).
In this case, it would have been prima facie obvious to one of ordinary skill in the art at the time the claimed invention was made to use the sequences of Chang in the CAR constructs suggested above because one of skill in the art would recognize that the sequences of Chang has been used in CAR constructs before, so using the sequences of Chang would be considered to be combining prior art elements according to known methods to yield predictable results.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
In the response, Applicant traverses the rejection and argues that Chang et al does not cure the deficiencies of the other references noted above.
These arguments are not found persuasive with respect to the other references as detailed above and incorporated herein.
Accordingly, after careful and complete consideration of Applicant’s response and the record as a whole, this rejection is being maintained.
Claim 68 is rejected under 35 U.S.C. 103(a) as being unpatentable over Cooper et al (WO 2013/074916 A1, IDS), Hoyos et al (Leukemia, 24, 1160-1170, 2010, of record) and Bertschinger et al (WO 2010/095031 A2, of record), as applied to claims 64 and 73-74 above, in further view of June et al (WO 2012/079000 A1, of record).
The previous combination teaches and suggests that which is set forth in the above 103 rejection.
June et al teach a using a 4-1BB sequence comprising the instant SEQ ID NO:42 in CARs (see entire document, e.g., abstract and see SEQ 23).
In this case, it would have been prima facie obvious to one of ordinary skill in the art at the time the claimed invention was made to use 4-1BB sequence of June in the CAR constructs suggested above because one of skill in the art would recognize that the 4-1BB sequence of June has been used in CAR constructs before, so using the 4-1BB sequence of June would be considered to be combining prior art elements according to known methods to yield predictable results.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
In the response, Applicant traverses the rejection and argues that June et al does not cure the deficiencies of the other references noted above.
These arguments are not found persuasive with respect to the other references as detailed above and incorporated herein.
Accordingly, after careful and complete consideration of Applicant’s response and the record as a whole, this rejection is being maintained.
Claim 70 is rejected under 35 U.S.C. 103(a) as being unpatentable over Cooper et al (WO 2013/074916 A1, IDS), Hoyos et al (Leukemia, 24, 1160-1170, 2010, of record) and Bertschinger et al (WO 2010/095031 A2, of record), as applied to claims 64 and 73-74 above, in further view of Sadelain et al (US 2004/0043401 A1, of record).
The previous combination teaches and suggests that which is set forth in the above 103 rejection.
Sadelain et al teach a using a CD3zeta sequence comprising the instant SEQ ID NO:40 in CARs (see entire document, e.g., abstract and see SEQ 14).
In this case, it would have been prima facie obvious to one of ordinary skill in the art at the time the claimed invention was made to use said CD3zeta sequence in the CAR constructs suggested above because one of skill in the art would recognize that said CD3zeta sequence has been used in CAR constructs before, so using said CD3zeta sequence would be considered to be combining prior art elements according to known methods to yield predictable results.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
In the response, Applicant traverses the rejection and argues that Sadelain et al does not cure the deficiencies of the other references noted above.
These arguments are not found persuasive with respect to the other references as detailed above and incorporated herein.
Accordingly, after careful and complete consideration of Applicant’s response and the record as a whole, this rejection is being maintained.
Claim 71 is rejected under 35 U.S.C. 103(a) as being unpatentable over Cooper et al (WO 2013/074916 A1, IDS), Hoyos et al (Leukemia, 24, 1160-1170, 2010, of record) and Bertschinger et al (WO 2010/095031 A2, of record), as applied to claims 64 and 73-74 above, in further view of Brenner et al (WO 2011/146862 A1).
The previous combination teaches and suggests that which is set forth in the above 103 rejection.
Brenner et al teach a using a caspase sequence comprising the instant SEQ ID NO:29 in T cells as a suicide gene (see entire document, e.g., abstract and see SEQ 9).
In this case, it would have been prima facie obvious to one of ordinary skill in the art at the time the claimed invention was made to use said caspase sequence in the CAR constructs suggested above because one of skill in the art would recognize that said caspase sequence has been used in T cells before as a suicide gene, so using said caspase sequence would be considered to be combining prior art elements according to known methods to yield predictable results.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
In the response, Applicant traverses the rejection and argues that Brenner et al does not cure the deficiencies of the other references noted above.
These arguments are not found persuasive with respect to the other references as detailed above and incorporated herein.
Accordingly, after careful and complete consideration of Applicant’s response and the record as a whole, this rejection is being maintained.
Conclusion
No claims are allowed. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Kochenderfer et al (J Immunother. 2009 September; 32(7):689-702, pages 1-26, of record) disclose CD19 chimeric antigen receptors made using sequences from antibody FMC63 (see page 3). Jensen (US 2012/0301447 A1, of record) disclose CD19 chimeric antigen receptors made using sequences from antibody FMC63 (see page 6).
All claims are drawn to the same invention claimed in the application prior to the entry of the submission under 37 CFR 1.114 and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 extension fee 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 Brad Duffy whose telephone number is (571) 272-9935. The examiner can normally be reached on Monday through Friday.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Julie Wu can be reached on (571) 272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Respectfully,
Brad Duffy
571-272-9935
/Brad Duffy/
Primary Examiner, Art Unit 1643
March 10, 2026