Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Detailed Action
This action is in response to the papers filed June 9, 2026.
Amendments
Applicant's amendments, filed June 9, 2026, is acknowledged. Applicant has cancelled Claims 5, 7-10, 13-15, 17-21, 23, 26-29, and 31-58, amended Claims 1-4, 12, 16, and 59, and added new claims, Claims 61-65.
Claims 1-4, 6, 11-12, 16, 22, 24-25, 30, and 59-65 are pending.
Election/Restrictions
Applicant has elected without traverse the following species, wherein:
i) the alternative toxin SEQ ID NO is SEQ ID NO:34, as recited in Claim 12;
ii) the alternative IL-13 domain SEQ ID NO is SEQ ID NO:29, as recited in Claim 3;
iii) the alternative transmembrane domain SEQ ID NO is SEQ ID NO:14, as recited in Claim 2;
iv) the alternative co-stimulatory domain SEQ ID NO is SEQ ID NO:23, as recited in Claim 4; and
v) the alternative CAR SEQ ID NO is SEQ ID NO:50, as recited in Claim 16.
Claims 1-4, 6, 11-12, 16, 22, 24-25, 30, and 59-65 are pending and under consideration.
Priority
This application is a 371 of PCT/US2021/021890 filed on March 11, 2021. Applicant’s claim for the benefit of a prior-filed application provisional application 62/988,199 filed on March 11, 2020 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Information Disclosure Statement
Applicant has filed an Information Disclosure Statement on June 9, 2026 that has been considered.
The information disclosure statements filed June 9, 2026 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because 37 CFR 1.98(b) requires that each item of information in an IDS be identified properly. Each publication must be identified by publisher, author (if any), title, relevant pages of the publication, and date and place of publication. The date of publication supplied must include at least the month and year of publication, except that the year of publication (without the month) will be accepted if the applicant points out in the information disclosure statement that the year of publication is sufficiently earlier than the effective U.S. filing date and any foreign priority date so that the particular month of publication is not in issue.
See also MPEP 707.05(e) for electronic documents, including, but not limited to:
(D) reference to the unique Digital Object Identifier (DOI) number, or other unique identification number, if known.
Bibliographic information provided must be at least enough to identify the publication. author, title and date. For books, minimal information includes the author, title, and date. For periodicals, at least the title of the periodical, the volume number, date, and pages should be given.
NPL citations have been lined through for being defective of one or more requirements.
The signed and initialed PTO Forms 1449 are mailed with this action.
Allowable Subject Matter
1. The prior indication of allowable subject matter is withdrawn for reasons discussed below.
Claim Objections
2. Claims 1 and 59 are objected to because of the following informalities:
Where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation, 37 CFR 1.75(i). See MPEP §608.01(m).
The multiple ‘wherein’ clauses should each be separated by line indentation.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
3. The prior rejection of Claims 2, 4, and 16 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of Applicant’s amendments to the claims to recite “the….sequence of”, which the Examiner finds persuasive.
4. The prior rejections of Claims 26 and 32 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, and 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, are withdrawn in light of Applicant’s cancellation of the claims.
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.
5. Claims 1-4, 6, 11-12, 16, 22, 24-25, 30, and 59-65 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Brown et al (WO 16/044811; Applicant’s own work; hereafter Brown-1; of record) in view of Barish et al (WO 17/066481; Applicant’s own work; hereafter Brown-2; of record), Nabors (2004; of record), and Zah et al (2016; of record).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
With respect to Claims 1, 3, 12, 59, and 62-63, Brown-1 is considered relevant prior art for having disclosed a chimeric antigen receptor comprising:
i) an IL-13 domain comprising the amino acid sequence of SEQ ID NO:29 (e.g. Figures 17 and 20);
ii) a linker;
iii) a spacer (e.g. IgG4 hinge domain);
iv) a CD28 transmembrane domain comprising the amino acid sequence of instant SEQ ID NO:14 (e.g. Table 2; Figure 20);
v) a CD28 co-stimulatory domain comprising the amino acid sequence of instant SEQ ID NO:23 (e.g. Table 3; Figure 20);
and
vi) a CD3zeta signaling domain (e.g. Figure 1).
Brown-1 disclosed wherein the IL-13 chimeric antigen receptor is useful for the treatment of glioma (e.g. [0054-55]).
Brown-2 is considered relevant prior art for having disclosed a chimeric antigen receptor comprising:
i) a chlorotoxin (Cltx) domain comprising the amino acid sequence of SEQ ID NO:34 (e.g. Figure 9);
ii) a linker;
iii) a spacer (e.g. IgG4 hinge domain);
iv) a CD28 transmembrane domain comprising the amino acid sequence of instant SEQ ID NO:14 (e.g. Table 2);
v) a CD28 co-stimulatory domain comprising the amino acid sequence of instant SEQ ID NO:23 (e.g. Table 3); and
vi) a CD3zeta signaling domain (e.g. Figure 1).
Brown-2 disclosed wherein the chlorotoxin domain (e.g. Figure 9, lower line) comprises the amino acid sequence of SEQ ID NO:34 (upper line), as shown below:
MCMPCFTTDHQMARKCDDCCGGKGRGKCYGPQCLCR
||||||||||||||||||||||||||||||||||||
MCMPCFTTDHQMARKCDDCCGGKGRGKCYGPQCLCR
Brown-2 disclosed wherein the chlorotoxin-containing chimeric antigen receptor is useful for the treatment of glioma (e.g. Abstract; [0019]).
While Brown-2 disclosed that examples of CAR tumor targeting domains include IL-13 CARs (e.g. [001]), Brown-2 do not disclose a reduction to practice of linking an IL-13 domain to a cytotoxin.
Nabors is considered relevant prior art for having taught that:
a) like Brown-1, the IL-13 receptor is expressed at high levels on glioma tumors (e.g. pg 521);
b) IL-13 fused to a cytotoxin has been used for the treatment of gliomas (e.g. pg 521); and
c) chlorotoxin binds specifically and with high affinity to tumors of the central nervous system, including gliomas (e.g. pg 522).
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 knowledg’able and well-read in the relevant literature and have the practical experience in molecular biology, cancer biology, and the creation of chimeric antigen receptors. Therefore, the level of ordinary skill in this art is high.
"A person of ordinary skill in the art is also a pe“son 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 "”he inferences and creative steps that a person of“ordinary skill in the art would employ." Id. at ___, 82 USPQ2d at 1396.
Zah et al is considered relevant prior art for having taught the synthesis of a bispecific chimeric antigen receptor comprising a first (e.g. anti-CD19) and second (e.g. anti-CD20) target binding domains, wherein the first and second target binding domains may be in either order, CD19xCD20 or CD20xCD19 (e.g. Figure 1c).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to modify the IL-13 chimeric antigen receptor to further comprise a chlorotoxin with a reasonable expectation of success because Applicant themselves (Brown-2) disclosed chlorotoxin-containing CARs for the treatment of glioma, examples of which include CAR tumor targeting domains include IL-13 CARs, and Nabors et al taught that:
a) like Brown-1, the IL-13 receptor is expressed at high levels on glioma tumors (e.g. pg 521);
b) IL-13 fused to a cytotoxin has been used for the treatment of gliomas (e.g. pg 521); and
c) chlorotoxin binds specifically and with high affinity to tumors of the central nervous system, including gliomas (e.g. pg 522).
Prior to the effective filing date of the instantly claimed invention, it also would have been obvious to one of ordinary skill in the art to substitute a first CAR glioma tumor targeting domain with a second CAR glioma tumor targeting domain, i.e. IL-13, in a chlorotoxin-containing CAR 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 CAR glioma tumor targeting domain with a second CAR glioma tumor targeting domain, i.e. IL-13, in a chlorotoxin-containing CAR because:
a) Applicant themselves previously disclosed IL-13-containing CARs for the treatment of glioma;
b) chlorotoxin-containing CARs are useful for the treatment of glioma, and
c) IL-13-toxin fusions were previously recognized to be useful for the treatment of glioma.
It is proper to "take account of the inferences and creative steps “hat a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, ”741,82 U’PQ2d 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 2, as discussed above, Brown-1 disclosed wherein the CAR comprises a CD28 transmembrane domain comprising the amino acid sequence of instant SEQ ID NO:14.
Brown-2 also disclosed wherein the CAR comprises a CD28 transmembrane domain comprising the amino acid sequence of instant SEQ ID NO:14 (e.g. Table 2), as shown below:
FWVLVVVGGVLACYSLLVTVAFIIFWV
|||||||||||||||||||||||||||
FWVLVVVGGVLACYSLLVTVAFIIFWV
With respect to Claim 4, as discussed above, Brown-1 disclosed wherein the CAR comprises a CD28gg* co-stimulatory domain comprising the amino acid sequence of instant SEQ ID NO:23.
Brown-2 also disclosed wherein the CAR comprises a CD28gg* co-stimulatory domain comprising the amino acid sequence of instant SEQ ID NO:23 (e.g. Table 3), as shown below:
RSKRSRGGHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS
|||||||||||||||||||||||||||||||||||||||||
RSKRSRGGHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS
With respect to Claim 12, Brown-2 disclosed wherein the chlorotoxin domain (e.g. [005], lower line) comprises the amino acid sequence of SEQ ID NO:34 (upper line), as shown below:
MCMPCFTTDHQMARKCDDCCGGKGRGKCYGPQCLCR
||||||||||||||||||||||||||||||||||||
MCMPCFTTDHQMARKCDDCCGGKGRGKCYGPQCLCR
With respect to Claim 6, Brown-2 disclosed wherein the Cltx-CAR may further comprise additional target binding domains, wherein the first and second target binding domains are separated by a linker domain comprising 1-10 amino acids (e.g. [007]).
Zah et al taught wherein the bispecific CAR comprises a linker domain of about 20 amino acids between the first and second target binding domains (e.g. pg 500, col. 2, (G4S)4 linker).
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 11 and 64, those of ordinary skill in the art immediately recognize that there are only two options: A before B, and B before A.
Furthermore, Zah et al taught the synthesis of a bispecific chimeric antigen receptor comprising a first (e.g. anti-CD19) and second (e.g. anti-CD20) target binding domains, wherein the first and second target binding domains may be in either order, CD19xCD20 or CD20xCD19 (e.g. Figure 1c).
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.”
One of ordinary skill in the art would understand how to design bi-specific chimeric antigen receptors, whereby the ordinary artisan could have pursued the known potential options with a reasonable expectation of success. The number of possible configurations from which to choose, to wit, two (2), is neither astronomical nor insurmountable, and given the guidance of Zah et al (bi-specific CAR), it would be only routine experimentation to determine which configuration, A before B, or B before A, yielded a desired result.
With respect to Claim 22, Brown-1 disclosed an expression vector comprising the nucleic acid encoding said IL-13-CAR (e.g. [009]).
Brown-2 disclosed an expression vector comprising the nucleic acid encoding said Cltx-CAR (e.g. [009]).
With respect to Claims 24 and 60, Brown-1 disclosed a population of human T or NK cells genetically modified to comprise and express the nucleic acid encoding said IL-13-CAR (e.g. [009-10]).
Brown-2 disclosed a population of human T cells genetically modified to comprise and express the nucleic acid encoding said Cltx-CAR (e.g. [009-10]).
With respect to Claims 25 and 61, Brown-1 disclosed the population of human T cells comprise central memory T cells (e.g. [009-10]).
Brown-2 disclosed the population of human T cells comprise central memory T cells (e.g. [009-10]).
With respect to Claim 30, Brown-1 disclosed a method of preparing IL-13-CAR human T cells, the method comprising the step of transducing a population of autologous or allogeneic human T cells (e.g. [0010]) with an expression vector encoding the nucleic acid encoding said IL13-CAR (e.g. [009]).
Brown-2 disclosed a method of preparing Cltx-CAR human T cells, the method comprising the step of transducing a population of autologous or allogeneic human T cells with an expression vector encoding the nucleic acid encoding said Cltx-CAR (e.g. [0016]).
With respect to Claims 26 and 32, Brown-1 disclosed a method of treating glioblastoma in a tumor xenograft mouse model, the method comprising the step of administering by intravenous or intracranial injection a population of human T cells genetically modified to express the IL13-CAR (e.g. Example 9).
Brown-2 disclosed a method of treating glioblastoma in a tumor xenograft mouse model, the method comprising the step of administering by an undisclosed route a population of human T cells genetically modified to express the Cltx-CAR (e.g. Example 12).
Zah et al taught a method of treating cancer in a tumor xenograft mouse model, the method comprising the step of administering by intravenous injection a population of human T cells genetically modified to express a bi-specific CAR (e.g. pg 499, col’s 1-2, Methods).
With respect to Claims 16 and 65, the claims recite the CAR amino acid sequence of SEQ ID NO:50.
Amino acids 1-112 of SEQ ID NO:50 are the SEQ ID NO:29 IL-13 domain disclosed by Brown-1.
Amino acids 128-163 of SEQ ID NO:50 are the SEQ ID NO:34 chlorotoxin domain disclosed by Brown-2.
Amino acids 394-420 of SEQ ID NO:50 are the SEQ ID NO:14 CD28 transmembrane domain disclosed by Brown-1 and Brown-2.
Amino acids 421-461 of SEQ ID NO:50 are the SEQ ID NO:23 CD28 co-stimulatory domain disclosed by Brown-1 and Brown-2.
SEQ ID NO:50 (upper line)
GPVPPSTALRYLIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIE
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
GPVPPSTALRYLIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIE
KTQRMLSGFCPHKVSAGQFSSLHVRDTKIEVAQFVKDLLLHLKKLFREGRFNGGGGSGGG
||||||||||||||||||||||||||||||||||||||||||||||||||||
KTQRMLSGFCPHKVSAGQFSSLHVRDTKIEVAQFVKDLLLHLKKLFREGRFN--------
GSGGGGSMCMPCFTTDHQMARKCDDCCGGKGRGKCYGPQCLCRESKYGPPCPPCPAPEFE
-------MCMPCFTTDHQMARKCDDCCGGKGRGKCYGPQCLCRESKYGPPCPPCPAPEFE
GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQ
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQ
FQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
FQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ
EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKS
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKS
RWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKMFWVLVVVGGVLACYSLLVTVAFIIFWV
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
RWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKMFWVLVVVGGVLACYSLLVTVAFIIFWV
RSKRSRGGHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS-------------------
|||||||||||||||||||||||||||||||||||||||||
RSKRSRGGHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSGGGKRGRKKLLYIFKQPFM
--------------------------GGGRVKFSRSADAPAYQQGQNQLYNELNLGRREE
EEEEGGCELGGGRVKFSRSADAPAYQQGQNQLYNELNLGRREE
YDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQ
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
YDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQ
GLSTATKDTYDALHMQALPPR
|||||||||||||||||||||
GLSTATKDTYDALHMQALPPR
Instant SEQ ID NO:50 does not comprise a 4-1BB intracellular signaling domain (KRGRKKLLYIFKQPFMEEEEGGCEL).
However, Brown-1 disclosed the presence of the 41BB domain in the IL-13 CAR is optional (e.g. Figure 14, lacking 41BB domain).
Similarly, Brown-2 disclosed the presence of the 41BB domain in the Cltx-CAR is optional (e.g. Figure 7, lacking 41BB domain).
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 an IL-13-chlorotoxin bispecific CAR lacking a 41BB intracellular signaling domain 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.” Those of ordinary skill in the art previously recognized that there are only two finite, predictable options, whereby the CAR does/does not comprise a 41BB intracellular signaling domain, and Applicant themselves demonstrated IL-13 CARs and chlorotoxin CARs that do/do not have 41BB intracellular signaling domain.
The GGGGSGGGGSGGGGS (syn. (Gly4-Ser)3) linker motif between the IL-13 domain and the chlorotoxin domain is not considered to be material to patentability.
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.
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).
Instant specification fails to disclose an element of criticality for the (Gly4-Ser)3 linker motif of SEQ ID NO:50, as opposed to (Gly4-Ser)4 linker motif of Zah et al.
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 there is no mention in Brown-2 that the chlorotoxin CAR includes an antigen-binding domain.
Applicant’s argument(s) has been fully considered, but is not persuasive. While it is acknowledged that the chlorotoxin CAR of Brown-2 (Figure 1; Abstract) does not also comprise an antigen-binding domain, Brown-2 disclosed the Cltx-CAR may further comprise additional glioma targeting domains (e.g. [007]).
Applicant argues that Brown-2 do not provide basis for the substitution proposed.
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 focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to modify the IL-13 chimeric antigen receptor to further comprise a chlorotoxin with a reasonable expectation of success because Applicant themselves (Brown-2) disclosed chlorotoxin-containing CARs for the treatment of glioma, examples of which include CAR tumor targeting domains include IL-13 CARs, and Nabors et al taught that:
a) like Brown-1, the IL-13 receptor is expressed at high levels on glioma tumors (e.g. pg 521);
b) IL-13 fused to a cytotoxin has been used for the treatment of gliomas (e.g. pg 521); and
c) chlorotoxin binds specifically and with high affinity to tumors of the central nervous system, including gliomas (e.g. pg 522).
Prior to the effective filing date of the instantly claimed invention, it also would have been obvious to one of ordinary skill in the art to substitute a first CAR glioma tumor targeting domain with a second CAR glioma tumor targeting domain, i.e. IL-13, in a chlorotoxin-containing CAR 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 sui“ability 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 CAR glioma tumor targeting domain with a second CAR glioma tumor targeting domain, i.e. IL-13, in a chlorotoxin-containing CAR because:
a) Applicant themselves previously disclosed IL-13-containing CARs for the treatment of glioma;
b) chlorotoxin-containing CARs are useful for the treatment of glioma, and
c) IL-13-toxin fusions were previously recognized to be useful for the treatment of glioma.
It is proper to "take account of the inferences and creative steps “hat a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, ”741,82 U’PQ2d 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).
Applicant argues that the cited prior art does not reduce to practice a CAR comprising a first and second glioma targeting domain.
Applicant’s argument(s) has been fully considered, but is not persuasive. The specification need not contain an example if the invention is otherwise disclosed in such manner that one skilled in the art will be able to practice it without an undue amount of experimentation. In re Borkowski, 422 F.2d 904, 908, 164 USPQ 642, 645 (CCPA 1970).
A reference contains an "enabling disclosure" if the public was in possession of the claimed invention before the date of invention. "Such possession is effected if one of ordinary skill in the art could have combined the publication's description of the invention with his [or her] own knowledge to make the claimed invention." In re Donohue, 766 F.2d 531, 226 USPQ 619 (Fed. Cir. 1985).
Applicant themselves (Brown-2) disclosed the Cltx-CAR may further comprise additional glioma targeting domains (e.g. [007]).
Zah et al successfully demonstrated a reduction to practice synthesizing a bispecific chimeric antigen receptor comprising a first (e.g. anti-CD19) and second (e.g. anti-CD20) target binding domains, wherein the first and second target binding domains may be in either order, CD19xCD20 or CD20xCD19 (e.g. Figure 1c).
Thus, no undue experimentation is required.
Applicant argues that the bispecific IL-13 and chlorotoxin CAR is activated when in contact with glioblastoma cell lines, at percentages not demonstrated by IL-13-only or chlorotoxin-only CARs (e.g. Figures 3A-C).
Applicant’s argument(s) has been fully considered, but is not persuasive.
Figure 3 only speaks to bispecific IL-13 and chlorotoxin CARs. There is no comparison to monospecific IL-13-only or chlorotoxin-only CARs.
Nevertheless, the Examiner provides the following references to rebut applicant’s arguments regarding the state of the prior art regarding bi-specific CARs. Note: the reference is not considered a part of the 103 rejection but are solely provided to rebut applicant’s argument(s).
Martyniszyn et al (CD20-CD19 Bispecific CAR T Cells for the Treatment
of B-Cell Malignancies, Human Gene Therapy 28(12): 1147-1157, available online December 5, 2017) is considered relevant prior art for having taught that the bi-specific CAR, e.g. CD19xCD20, had equal to, if not greater than, activity against the target cell than monospecific CD19-only or CD20-only CARs (e.g. Figure 2B, 3C; Figure 4, legend, “The anti-CD20-CD19 CAR T cells eliminated CD19+CD20+/– leukemia more efficiently than anti-CD20 CAR T cells”; Figure 4C; pg 1156, Conclusion, “the anti-CD20-CD19 bispecific CAR T cells proved superior in controlling CD19+ CD20+/- leukemia compared to CD20 CAR T cells”). Thus, Applicant’s asserted beneficial effect of a bispecific CAR as compared to a monospecific CAR is not considered to be surprising or unexpected.
Citation of Relevant Prior Art
6. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Ahmed et al (U.S. 2013/0280220) is considered relevant prior art for having disclosed a bispecific chimeric antigen receptor (e.g. Figure 1) comprising an IL-13 receptor binding domain and a second tumor antigen binding domain (e.g. [0012, 210, 217]).
Jensen et al (U.S. 2015/0038684) is considered relevant prior art for having disclosed a bispecific chimeric antigen receptor (e.g. Figures 1-2) comprising an IL-13 binding domain and a second tumor antigen binding domain (e.g. [0073, 75]).
Lim et al (U.S. 2016/0264665) is considered relevant prior art for having disclosed a bispecific chimeric antigen receptor comprising an IL-13 binding domain and a second tumor antigen binding domain (e.g. [00152, 214, 221-222, 227]).
Thus, prior to the effective filing date of the instantly claimed invention, those of ordinary skill in the art were previously aware of the scientific and technical concept of bi-specific CARs comprising an IL-13 domain.
Conclusion
7. No claims are allowed.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638
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