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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 3/28/2025 has been entered.
Claim Status
Claims 2-3, 5, 7-79, 82-96, 99-100, 103-104, 108-116, 118-120, 122-127 and 129 were canceled.
Claims 1, 4, 6, 80-81, 97-98, 101-102, 105-107, 117, 121 128, and 130-133 are pending.
Claims 97-98, 107, 117, 121 and 131-133 stay withdrawn from further consideration (see below).
Claims 1, 4, 6, 80-81, 101-102, 105-106, 128, and 130 are under consideration.
Election/Restrictions
Applicant traversed the withdrawal of claims 131-133. The traversal is on the ground(s) that claims 131-133 are directed to elected Group II. This is not found persuasive because claims 131-133 comprise new recruitment domain and have different structure. Furthermore, claims 132-133 is drawn to a “system” comprising two different fusion proteins each of which comprises new recruitment domain. Therefore, claims 131-133 constitutes a different invention having different structure. Applicant further argued that there is no serious search burden. However, there is serious search burden for the new structure comprising new recruitment domain.
The requirement is still deemed proper and is therefore made FINAL.
Withdrawn Rejections
Rejection of Claims 1, 4, 8, 80, 128 and 130 on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 11059864 is withdrawn. Applicant amended the claim 1 and provided a persuasive argument, thereby obviating this rejection/objection. Furthermore, patent’864 does not claim construct wherein protease, cleavage site, and degradation sequence are linked to one another as claimed by amended claim 1. For example, claim 10 of patent’864 claims a system wherein the first polypeptide comprises a protease and the second polypeptide comprises degron domain. Therefore, the structure of instant invention is different from that of patent’864.
NEW - Claim Objections
(based on reconsideration)
Claim 6 is objected to because of the following informalities: claim 6 recites acronyms TCR, BCR, RTK and TNFR2. Acronyms must be spelled out on their first use. Appropriate correction is required.
Claim 128 is objected to because of the following informalities: conjunction “or” should read “and” for proper Markush group format. See MPEP 2173.05(h) for proper Markush group format. Appropriate correction is required.
NEW - Claim Rejections - 35 USC § 112
(based on reconsideration)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 6 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 6 depends from claim 1 and claim 1 recites that the fusion protein comprises a chimeric antigen receptor. Instant specification disclosed “The term, "chimeric antigen receptor" or alternatively a "CAR" as used herein refers to a polypeptide or a set of polypeptides, which when expressed in an immune effector cell, provides the cell with specificity for a target cell, typically a cancer cell, and with intracellular signal generation” (paragraph 105, page 15). Instant specification further disclosed “CARs, generally, are artificial immune cell receptors engineered to recognize and bind to an antigen expressed by tumor cells” (paragraph 142, page 39). Furthermore, it is well known in the art that “antigen” is recognized by “antibody”. Therefore, according to the definition of CAR disclosed by instant specification and as known in the art, one of ordinary skill in the art would understand that CAR comprises extracellular antigen binding domain of antibody, antigen binding fragment or at least extracellular antigen binding domain of immunoglobulin superfamily.
It is well known in the art that TCR, BCR, a cytokine receptor, RTK receptor and immunoglobulin superfamily receptor recited by claim 6 are members of immunoglobulin superfamily. However, serine/threonine kinase receptor, hormone receptor and TNFR-superfamily of receptor are not members of immunoglobulin superfamily.
Furthermore, as discussed above, CAR recognizes cancer cell by binding to cancer-specific antigen expressed on cell surface. While TCR recognize antigen presented on cancer cell surface, all other receptors recited by claim 6 bind to soluble protein which is not expressed on cell surface. For example, cytokine receptor binds to a cytokine which is secreted out of cell, not expressed on the cell surface.
Therefore, it is unclear whether Applicant intends to recite “chimeric antigen receptor” as defined by instant specification. It is also unclear how CAR comprising extracellular domain of BCR, a cytokine receptor, RTK receptor, serine/threonine kinase receptor, hormone receptor, immunoglobulin superfamily receptor and TNFR-superfamily receptor can recognize cancer cell by binding to cancer-specific antigen expressed on cancer cell.
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 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.
Claims 1, 4, 80-81, 101-102, 105-106, 128 and 130 are rejected under 35 U.S.C. 103 as being unpatentable over LIN (WO 2017/004022; IDS) and Golosov (WO2017/181119; IDS).
Regarding claim 1, LIN teaches a fusion protein comprising degron, protease, protease cleavage site, and protein of interest (figure 1A; claim 4). LIN teaches that protease is NS3, the cleavable linker comprises an NS3 protease cleavage site, and the NS3 cleavage site comprises an NS3/NS4A junction cleavage site (claims 5-7).
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Regarding new limitation “a self-excising degron operably linked to the C-terminus of the CAR” and “wherein the self-excising degron comprises the repressible protease, the cognate cleavage site, and the degradation sequence physically linked to one another in sequential order from the N-terminus to the C- terminus”, LIN teaches “The fusion polypeptides may be designed for N-terminal or C- terminal attachment of the degron to the polypeptide of interest”. LIN teaches different orientation of degron system (Figure 9B; reproduced below).
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One of ordinary skill in the art would be able to envision all possible orientation of degron system relative to protein-of-interest: from N-terminus to C-terminus, (i) (protein-of-interest) - cleavage site – protease - degradation sequence; (ii) (protein-of-interest) – protease - cleavage site - degradation sequence; (iii) (protein-of-interest) - cleavage site - degradation sequence - protease; (iv) degradation sequence – protease - cleavage site – (protein-of-interest); (v) degradation sequence - cleavage site – protease – (protein-of-interest); and (vi) protease - degradation sequence - cleavage site – (protein-of-interest). One of ordinary skill in the art would be motivated to try these different orientations to find optimal construct for the best efficiency because it was well known in the art that different orientation of components in the fusion protein may give a different efficiency of the fusion protein. It would have been obvious to one of ordinary skill in the art to try the finite number of identified predictable solutions through routine experimentation. Making protein construct in the different orientation of components was routine experimentation to one of ordinary skill in the art at the time the claimed invention was filed.
Regarding claim 80, LIN teaches that protease inhibitor is simeprevir (claim 40).
Regarding claim 81, LIN teaches degradation sequence SEQ ID NO: 1 which is 100% identical to instant SEQ ID NO: 1 (Result 1 of 1.rag).
Result 1 of 1.rag
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Regarding claim 101, LIN teaches host cell comprising fusion protein (claims 4, 26, 27, 33).
Regarding claims 105-106, LIN teaches a composition comprising pharmaceutically acceptable excipient.
However, LIN does not teach that the protein of interest is CAR.
Regarding claim 1, 4, 128, and 130, GOLOSOV teaches fusion protein comprising CAR, protease cleavage site, and degron (figure 25; reproduced below). GOLOSOV teaches “Chimeric antigen receptors can include, e.g., in a N-terminal to C-terminal direction, an antigen binding domain, a transmembrane domain, and one or more intracellular signaling domains. The signaling domain may include one or more primary signaling domains (e.g., a CD3-zeta stimulatory domain) and, optionally, one or more costimulatory signaling domains. … In certain of the above embodiments, the antigen binding domain is an scFv.” The claim limitation “additional intracellular signaling domain” of claim 130 corresponds to costimulatory signaling domain taught by GOLOSOV.
Regarding claim 102, GOLOSOV teaches “the immune cell comprising the fusion protein”. GOLOSOV teaches “In another aspect, the invention features a cell, e.g., a host cell including any one of the foregoing fusion proteins. In some embodiments, the cell, e.g., the host cell, is an immune cell, e.g., an immune effector cell. In some embodiments, the cell is a T cell or an NK cell”.
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It would have been obvious to one of ordinary skill in the art before the filing date of the claimed invention to have substituted “protein of interest” from fusion protein of LIN with CAR to make controllable CAR comprising degron and CAR because one of ordinary skill in the art would be motivated to apply control mechanism taught by LIN to CAR system because LIN teaches that fusions of a degron to a protein of interest will be especially useful when control over protein production with minimal structural modification is desired (abstract) and because side effects associated with CAR (e.g. cytokine release syndrome) is well known in the art and therefore control over CAR is especially needed to decrease the side effect. The degron system of Lin is OFF switch because the whole fusion protein is degraded in the presence of small molecule (see Figure 1A of Lin reproduced above). Instant invention is also OFF switch (see instant Figure 1B). It is well known in the art that overtreatment with CAR can cause side effect (e.g. cytokine release syndrome) and the production of CAR in the engineered T-cell needs to be down regulated when enough treatment is already performed in the patient. Thus, one of ordinary skill in the art would be motivated to apply OFF switch of LIN to CAR because Lin teaches useful OFF switch needed for CAR and because Golosov teaches that CAR can be effectively fused to the degron system. Therefore, the invention as a whole would have been obvious to one of ordinary skill in the art.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success because LIN teaches OFF switch can be effectively applied to protein of interest when its production needs to be down regulated. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 1, 4, 6, 80-81, 101-102, 105-106, 128 and 130 are rejected under 35 U.S.C. 103 as being unpatentable over LIN (WO 2017/004022; IDS) and Golosov (WO2017/181119; IDS) as applied to claims 1, 4, 80-81, 101-102, 105-106, 128 and 130 above, and further in view of Walseng et at (TCR-based Chimeric Antigen Receptor. Sci Rep 7, 10713 (2017) cited previously by examiner)
Regarding claims 1, 4, 80-81, 101-102, 105-106, 128 and 130, teachings of LIN and Golosov were discussed above.
However, LIN and Golosov do not teach TCR-based chimeric antigen receptor with degron.
Regarding claim 6, Walseng teaches “Although very potent, CAR recognition is limited to membrane antigens which represent around 1% of the total proteins expressed, whereas TCRs have the advantage of targeting any peptide resulting from cellular protein degradation. … We have fused a soluble TCR construct to a CAR-signaling tail and named the final product TCR-CAR. We here show that, if expressed, the TCR-CAR conserved the specificity and the functionality of the original TCR. In addition, we demonstrate that TCR-CAR redirection was not restricted to T cells. Indeed, after transduction, the NK cell line NK-92 became TCR positive and reacted against pMHC target. This opens therapeutic avenues combing the killing efficiency of NK cells with the diversified target recognition of TCRs” (abstract).
It would have been obvious to one of ordinary skill in the art before the filing date of the claimed invention to have replaced the extracellular protein binding domain portion of the fusion protein of LIN and Golosov with TCR portion of TCR-CAR of Walseng because one of ordinary skill in the art would be motivated to make a controllable TCR-CAR in order to utilize the diversified target recognition of TCRs together with the killing efficiency of NK cells as taught by Walseng. Therefore, the invention as a whole would have been obvious to one of ordinary skill in the art.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success because Walseng teaches that the TCR-CAR conserved the specificity and the functionality of the original TCR. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
In the response filed on 3/28/2025, Applicant argued at page 9-10,
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Applicant's arguments have been fully considered but they are not persuasive. Although Lin mentioned the specific position of the cleavage site, it is their preference. Lin clear said, “The position of the cleavage site in the fusion is preferably chosen to allow release of the polypeptide of interest from the fusion protein essentially unmodified or with little modification (e.g., less than 10 extra amino acids)”. Lin does not provide any rational that protease must not be retained to the protein-of-interest. Instant application does not provide any benefit of the construct which retains the protease after cleavage (i.e. right three constructs over left three constructs in instant Figure 2). As shown in instant Figure 2, instant application also conceived both cases where the protease is cleaved off (left three of Figure 2) and is retained (right three of Figure 2). Because instant specification did not disclose any benefit of the construct where the protease is retained after cleavage, the orientation recited by amended claim 1 is just one of six possible orientations mentioned in rejection above (i.e. option (ii) of presented six options) and obvious to one of ordinary skill in the art. One of ordinary skill in the art would not envision that the retained protease will inhibit the function of CAR because there is no evidence that suggests the interaction between retained protease and CAR. It is known that protease interacts with cleavage site amino acid sequence and cleaves this cleavage site. There is no indication that protease will interact with CAR and will inhibit or enhance the function of CAR if protease is retained after cleavage. If the six possible options of positioning of components of degron system is not obvious, we will have to issue six independent patents to all six constructs of six options (options (i) – (vi) presented above in rejection) just because they have different positioning of components. Making protein construct in the different orientation of components was routine experimentation to one of ordinary skill in the art at the time the claimed invention was filed. Applicant needs to prove non-obviousness by providing evidence of benefit of the claimed construct comprising specific orientation of components over other possible constructs comprising other orientations.
Conclusion
No claim is allowed.
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/CHEOM-GIL CHEONG/Examiner, Art Unit 1645
/GARY B NICKOL/Supervisory Patent Examiner, Art Unit 1645