DETAILED ACTION
The present application is being examined under the pre-AIA first to invent provisions.
Applicant's amendment and remarks, filed 8/11/26, are acknowledged.
Claims 1-4, 12-17 have been amended.
Claims 1-4, 6-20 are pending.
Claims 4, 6-12, 15-20 are withdrawn from further consideration pursuant to 37 CFR 1.14209 as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1-3 and 13-14 are under examination.
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.
Claims 1-3 and 13-14 are 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 1 is indefinite, since the scope of the claimed antibodies or fragments thereof which bind to “a non-conserved region” of the extracellular domain of the CAR is unclear an indefinite. The specification on page 27 discloses that the molecule of the drug-molecule conjugate can be an antibody, and can bind to any portion of the CAR, for example to the antigen binding region or linker region. The specification on page 28 discloses that using a non-conserved immunogenic portion can produce antibodies specific for the non-conserved region thereby producing antibodies that do not cross-react with other proteins which can share one or more conserved portions. The specification on page 28 also discloses that based upon the disclosure provided, the non-conserved regions of an antigen of interest can be used to produce antibodies that are specific only for that antigen and do not cross react non-specifically with other proteins, including other types of CARs. The scope of the claims is unclear. For example, would the claims encompass antibodies that bind to a human CD8a hinge domain of a CAR, that do not cross-react with other CD8 homologs from rats or mice? In that instance, the antibodies would not be cross-reactive, and would bind to a region of CD8 that is “non-conserved” between species. However, the antibodies would bind naturally occurring human CD8a, that is also expressed by human T cells. Would that mean it is excluded from the claims, since the antibodies would bind to a CD8a hinge portion that is also present in CD8 on the T cells, meaning it is “conserved” between the CAR and the natural CD8. For example, are the claims limited to antibodies that bind to the idiotype of antigen binding region of the CAR? Would the claims encompass antibodies that bind to a linker region that is present in the CAR scFv portion? On the one hand, said linker region could be considered “non-conserved” with respect to other proteins naturally expressed by T cells. On other hand, identical scFV linker regions are used in numerous different types of CAR with different antigen specificities. Would such a linker region be considered “conserved” between different types of CAR, and therefore be outside of the claim scope? The scope of the claims cannot be established.
Applicant’s arguments filed 8/11/26 have been fully considered, but they are not persuasive.
Applicant argues that a person of ordinary skill in the art would understand the meaning of the phrase “non-conserved region”. Applicant cites Van Zelm as evidence, which identifies conserved and non-conserved position within CD19 family members.
The issue is not that the term non-conserved is indefinite per se. Van Zelm teaches comparing sequences of a of homologous proteins, such as CD19 to determine what is conserved or non-conserved between them. However, the present claims are not directed to a “non-conserved” region of CD19, but rather they are directed to a “non-conserved” region of an extracellular domain of a CAR. Chimeric antigen receptors are artificially constructed proteins created by linking modular domains that include non-naturally occurring elements, such as linkers, scFV containing VH/VL regions, as well as hinge domains from naturally occurring proteins, such as CD8. It is not clear what a “non-conserved” region of a CAR, which is modularly constructed from different heterologous components, would encompass. For example, would the claims encompass an antibody that binds to an artificial linker region in the scFV of the claimed CAR? On the one, a non-naturally occurring linker would not be found naturally in other proteins, and could therefore be considered a “non-conserved” sequence. On the other hand, the same linkers are used in many different CAR constructs, and hence could also be considered a conserved region in CAR constructs. Is a linker a conserved or non-conserved element of a CAR? Would the claims encompass an antibody that binds the idiotype of the particular scFV of a CAR? In this situation, the antibody would bind to only a particular CD19 scFV but not other CD19 scFV, i.e. it binds to a non-conserved region of CD19 binding scFV. However, Applicant has argued below that an idiotype is not a non-conserved region of a CAR. The scope of the claims is unclear and indefinite.
The following is a quotation of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), first paragraph:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3 and 13-14 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. Specifically, there is insufficient written description to demonstrate that applicant was in possession of the claimed genus of drug molecule conjugates.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See MPEP 2163.
The instant claims are drawn to a genus of drug-molecule conjugates comprising an antibody or fragment thereof which binds to an extracellular domain of a CAR comprising a CD8a hinged domain and CD19 scFv antigen binding domain, wherein the antibody or fragment thereof binds to a non-conserved region of the extracellular domain of the CAR. The claims require that the drug-molecule functions to regulate activity a CAR T cell, with dependent claims reciting that the conjugate must also function to be internalized and result in drug mediated cell death. The claims encompass a huge genus of structurally antibodies that bind to a huge genus of structurally and functionally distinct CAR domains. For example, the claims could encompass antibodies that bind to non-conserved regions of any CD8a hinge domain, non-conserved linker domains within the scFV antigen binding domain, or against the unique idiotype of a genus of CD19 scFV. Thus, the claims encompass antibodies that function to bind to an essentially unlimited genus of structurally and functionally distinct CAR domains. See, for example, Rabia, 2018, which teaches that the maximal chemical diversity of antibodies is unimaginably large and is extremely challenging to define the sequence determinant of antibody specificity (see page 4). See also Janeway, which teaches that the antibody repertoire in humans is at least 1011, with a large degree of diversity in both heavy and light chains. The claims encompass a genus of antibodies that bind to a genus of unique CD19 antibody idiotypes, wherein the idiotype repertoire could be as large as 1011, for example. In effect, the claims would encompass antibodies that function to bind to unique CD19 scFV CAR or novel linker regions that have not even been invented yet. The specification does not identify the actual structure of any species of antibodies that bind to an extracellular domain of CAR comprising a CD8a hinge and CD19 scFV antigen binding domain.
The instant application has not provided a sufficient description showing possession of the necessary functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus of drug-molecule conjugates encompassing various structures, specificities and functions. Further, the Court has interpreted 35 U.S.C. §112, first paragraph, to require the patent specification to “describe the claimed invention so that one skilled in the art can recognize what is claimed. Enzo Biochem, Inc. v. Gen-Probe Inc, 63 USPQ2d 1609 and 1618 (Fed. Cir. 2002).
In evaluating whether a patentee has fulfilled this requirement, our standard is that the patent’s “disclosure must allow one skilled in the art ‘to visualize or recognize the identity of’ the subject matter purportedly described.” Id. (quoting Regents of Univ. of Cal. v. Eli Lilly & Co., 43 USPQ2d 1398 (Fed Cir. 1997)).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
Also, it is noted that the Court has held that the disclosure of screening assays and general classes of compounds was not adequate to describe compounds having the desired activity: without disclosure of which peptides, polynucleotides, or small organic molecules have the desired characteristic, the claims failed to meet the description requirement of § 112. See University of Rochester v. G.D. Searle & Co., lnc., 69 USPQ2d 1886,1895 (Fed. Cir. 2004).
Meeting the written description threshold requires showing that the applicant was in “possession” of the claimed invention at the time of filing. Vas-Cath, 935 F.2d at 1563-1564. Support need not describe the claimed subject matter in exactly the same terms as used in the claims. Eiselstein v. Frank, 52 F.3d 1035, 1038 (Fed. Cir. 1995). This support cannot be based on obviousness reasoning – i.e., what the written description and knowledge in the art would lead one to speculate as to modifications the inventor might have envisioned, but failed to disclose. Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997). Ariad points out, the written description requirement also ensures that when a patent claims a genus by function, the specification recites sufficient materials to accomplish that function - a problem that is particularly acute in biological arts." Ariad, 598 F.3d at 1352-3. Note the following Court Decisions regarding the written description of antibodies, in particular, in the context of the current claims.
Given the claimed broadly class of molecules, in the absence of sufficient disclosure of relevant identifying characteristics, the patentee must establish “a reasonable structure-function correlation” either within the specification or by reference to the knowledge of one skilled in the art with functional claims. AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014) and the specification at best describes plan for making antibodies with the “limitations above” and then identifying those that satisfy claim limitations, but mere “wish or plan” for obtaining claimed invention is not sufficient. Centocor Ortho Biotech Inc. v. Abbott Laboratories, 97 USPQ2d 1870 (Fed. Cir. 2011). There is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed molecules or antibodies to demonstrate possession. Also, see Amgen Inc. v. Sanofi, Aventisub LLC, No. 2017-1480 (Fed. Cir. 2017). Thus, one of skill in the art would conclude that the specification fails to provide adequate written description to demonstrate that Applicant was in possession of the claimed genus. See Eli Lilly, 119 F. 3d 1559, 43, USPQ2d 1398.
Applicant’s arguments filed 8/11//26 have been fully considered, but they are not persuasive.
Applicant argues that the genus of antibodies encompassed by the claims was well-known in the art at the time of filing, citing as evidence WO 2009/052431.
The cited reference described CD19 binding CAR. The present claims are not directed to CD19 binding CAR, but rather to a genus of antibodies that bind to a CD19 binding CAR. Applicant’s evidence discloses the structure of potential antigens (CD19 CAR) to which the claimed antibodies bind, but this does not provide any information as to the structure of the antibodies themselves.
Applicant cites Van Zelm to establish that one could recognize which regions of CD19 are conserved or non-conserved.
The instant claims are not directed to an antibody that binds a non-conserved region of CD19, but rather to a non-conserved region of a CAR that binds CD19. No species are disclosed. The specification does not disclose a correlation between structure and function, does not disclosure relevant identifying characteristics, nor does it disclose a representative number of species.
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.
Claim 1-3 and 13-14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Oliventsein, 1993, in view of DiJoseph, 2007, Ping, 1999, and US 20030215453, as evidenced by Classon, 1992.
Olivenstein teaches OX-8 antibody for use in vivo for depleting cells expressing CD8. As evidenced by Classon, the OX-8 antibody binds to the hinge region of rat CD8a, including in chimeric proteins, wherein said the epitope bound by the antibody is: SIITKPVTRAPTPVPPPTGTPRPL (see page 221, in particular). Said rat hinge region can be considered a non-conserved region to the extent that it shares very little homology with, for example, human CD8 hinge (see attached alignment).
The reference differs from the claimed invention in that it does not explicitly teach said OX-8 antibody conjugated to calicheamicin.
DiJoseph teaches that antibodies can be conjugated to a cytotoxic agent to deplete cells targeted by the antibody (See page 1108, in particular). DiJoseph teach that the toxin can be a bacterial toxin or that calicheamicin is a potent cytotoxic agent that can be conjugated to depleting antibodies to maximize toxicity to the targeted cell (See page 1108, in particular). See also the ‘453 publication teaches that antibodies can be conjugated to a toxin to destroy targeted cells, and that the toxins can be bacterial toxins or calicheamicin (see paragraphs 70 and 170, in particular). The ‘453 publication teaches conjugate via SPDP (see paragraph 82).
Ping teaches conjugating anti-CD8 antibodies to toxin to deplete CD8 expressing cells.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to conjugate the OX-8 antibody of Olivenstein, to a cytotoxic agent such as calicheamicin, as taught by DiJoseph, the ‘453 publication, and Ping. The ordinary artisan at the time the invention was made would have been motivated to do so with a reasonable expectation of success, because Di Joseph and the ‘453 publication teaches that calicheamicin is a potent cytotoxic agent that can be conjugated to depleting antibodies to maximize toxicity to the targeted cell, and as taught by Ping, CD8 antibodies were known to be amenable to conjugation to a toxin to provide for depletion of CD8 expressing cells. Furthermore, selecting from known means of linking antibodies to calicheamicin, such as by using SPDP conjugation would involve choosing among a finite number of predictable options which could be pursued with a reasonable expectation of success. A person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (see KSR International Co. V. Telefex Inc 82 USPQ2d 1385).
The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006). In the instant case, the reason for creating the antibody conjugate would be to deplete CD8 T cells. However, the function of targeting CAR would be a latent property/intended use of the antibody made obvious above. For example, the antibody made obvious above could be used for targeted regulation of CAR T cell comprising a rat CD8a hinge and the other CAR elements of the instant claims.
Applicant’s arguments filed 8/11/26 have been fully considered, but they are not persuasive.
Applicant argues that the cited references do not teach that the antibody binds to a non-conserved region of the extracellular domain of the CAR, nor the recited regulation of CAR T cell activity.
As noted above, the prior art teaches that the antibody binds to an epitope of rat CD8a hinge that is non-conserved, i.e. it is present in rat CD8 but not in human CD8. Thus, this meets the limitation of “non-conserved” region of a CAR, since the claims broadly encompass CAR comprising any CD8a hinge (which would include rat). Regarding the function of the antibody to regulate activity of a CAR, the prior art teaches that the antibody can deplete or kill cells expressing said CD8 epitope, including chimeric proteins, and it therefore stands to reason that the antibody would also deplete/kill i.e. “regulate activity” of a cell expressing a CAR comprising said rat CD8a hinge domain. Applicant provides no arguments or reasoning as to why this is not correct.
Applicant argues that Lehner and James are not evidence of CAR internalization, since these references document CAR internalization after ligand binding, but not after engagement with an antibody.
As initial matter, only claim 2 requires internalization. The references provide evidence that CARs can be internalized upon ligand binding, and it would therefore be expected that the antibodies, which also bind to the extracellular ligand binding domain, would be internalized. Furthermore, the further property of being internalized would also be an inherent or latent property of the antibodies of the prior art.
Claims 1-3 and 13-14 is/are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Ramos et al., in view of Rossig et al., 2002 , US 4,792,447, US 20030215453 (all of record), and Lehner, Feb. 2012..
Ramos et al. describes chimeric antigen receptors which comprise an extracellular domain comprising a hinge portion and an scFV portion of an antibody that binds to a tumor antigen (see page 855-856 in particular). Ramos et al. teach that such scFV containing CAR can be introduced into T cells to create a population of cells for therapy that all comprise the CAR and can persists in vivo in the treated subjects. Ramos et al. specifically teach CARs that comprise an scFV region targeting CD19 (see Table 2, in particular). Ramos et al. teach that in the case of any untoward effects related to introduction of CAR modified T cells, it would be desired to have a safety mechanisms that would allow elimination of such CAR expressing T cells from the subject (see page s866-867, in particular).
The references do not teach an antibody binding to said CAR expressing T cells that is conjugated to a drug.
Rossig et al. teach a chimeric antigen receptor comprising an scFV targeting portion that can be expressed at the surface of T cells for use in adoptive immunotherapy. Additionally, Rossig et al. teach an idiotype specific antibody that binds to the idiotype portion of the scFV chimeric receptors, and teaches that said antibody can bind to the surface of cells expressing said chimeric receptor (see page 2011, in particular).
The ‘447 publication teaches producing antibody toxin conjugates, wherein the antibody has specificity for the idiotype region of the variable portion of an immunoglobulin, such that it recognizes the unique region of an immunoglobulin produced by a given clone (i.e. a region of an immunoglobulin found with an scFV, see column 4, in particular). The ‘447 publication teaches that said antibody toxin conjugates can be introduced into a host containing cells expressing the variable determinants or idiotype, and allows selective targeting of cells expressing the idiotype with the toxin and destruction of said cells (see abstract, and column 3-5, in particular). The ‘447 patent further teaches that the toxin can be ricin or any toxic agent including cytotoxic and carcinostatic drugs (see column 4, in particular).
The ‘453 publication teaches that toxins used for conjugation to antibodies for destroying targeted cells can be ricin or other chemotherapeutic agents such as calicheamicin (see paragraph 170, in particular). The ‘453 publication teaches conjugation via SPDP (see paragraph 82).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to produce an anti-idiotype toxin conjugate antibody, as taught by the ‘447 publication, the ‘453 publication, and Rossig, with specificity for the idiotype of the scFV of the CAR receptors taught by Ramos et al.. The ordinary artisan at the time the invention was made would have been motivated to do so to target the idiotype of the scFv domain of the CAR expressing cells for destruction, since Ramos et al. teach the desirability of having a means of eliminating CAR expressing T cells from a subject for safety reasons. Said idiotype specific antibody would uniquely react with a variable portion of an scFV, i.e. a non-conserved region. Furthermore, the ordinary artisan would have a reasonable expectation of success in targeting CAR expressing cells with such an anti-idiotype antibody conjugate as taught in the ‘447 patent, since Rossig et al. teach that anti-idiotype antibodies can bind to a scFV containing CAR expressed at the cell surface. See also Lehner, which teaches that it is recognized in the art that CAR receptors are internalized upon ligand binding, further providing a reasonable expectation of success for the limitations of claim 2. Furthermore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to use calicheamicin, as taught by the ‘453 publication, as the toxin in the antibody toxin conjugates. Selecting from the known toxins such as ricin or chemotherapeutic/carcinostatic agents including calicheamicin that can be used for antibody conjugation would involve choosing among a finite number of predictable options which could be pursued with a reasonable expectation of success. A person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (see KSR International Co. V. Telefex Inc 82 USPQ2d 1385).
Applicant’s arguments filed 8/11/26 have been fully considered, but they are not persuasive.
Applicant argues that an anti-idiotype specific antibody recognizes the unique paratope, or antigen binding stie, of a particular antibody clone, but this does not mean that it binds to a non-conserved region of the extracellular domain of a CAR. Applicant argues these are not the same axis of comparison, since an antibodies idiotype is unique because it differs from other antibodies variable regions, which is a property independent of whether a given region of a CAR is conserved or non-conserved. Applicant therefore concludes that the prior art does not teach an antibody that binds to “non-conserved region” of a CAR.
The antibody made obvious by the prior art binds to non-conserved regions of an antibody variable region, i.e. the paratope or idiotype. The CAR of the present claims comprises an scFV binding domain, which is comprised of an antibody variable region binding region, i.e. it comprises an antibody paratope or idiotype of a given antibody. If the idiotype is a non-conserved region of an antibody variable binding region, and a CAR comprises said antibody variable binding region, then said idiotype would also be considered a non-conserved region of a CAR comprising an scFV. The antibody of the prior art would bind selectively to only CAR comprising scFV having said idiotype, and not to other CAR constructed with different scFV idiotypes. This would be within the scope of an antibody that binds to a non-conserved region of an extracellular domain of a CAR.
No claim is allowed.
THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any 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 date of this final action.
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Amy E. Juedes
Patent Examiner
Technology Center 1600
/AMY E JUEDES/Primary Examiner, Art Unit 1644
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