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
The response filed September 12, 2025, is acknowledged and has been entered. No claims have been amended.
Claims 44-72 and 75-77 are pending.
Claims 50-57 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 44-49, 58-72 and 75-77 are under examination. Group I, drawn to a drawn to a chimeric antigen receptor (CAR) comprising a polypeptide comprising:(a) an extracellular antigen binding domain comprising a first single-domain antibody (sdAb) specifically binding to a first antigen and a second single domain antibody (sdAb) specifically binding to a second antigen, wherein each of the first and second sdAb is a VHH domain; (b) a transmembrane domain; and (c) an intracellular signaling domain is under consideration. The species of a first antigen of BCMA and a second antigen of BCMA are under consideration.
Information Disclosure Statement
The information disclosure statement has been considered.
Claim Rejections 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 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 44-47, 58-60, 62-72 and 75-77 are rejected under 35 U.S.C. 103 as being unpatentable over Jensen, Michael (WO 2013/123061 A1, IDS) and June et al (US 2014/0099340 A1, IDS).
With respect to the claims, Jensen teaches chimeric antigen receptors (CAR) comprising, in the following order, a signal sequence, 2 or more antibodies or other antigen-binding domains linked together (two antigen-specific targeting regions (ASTR) with a peptide linker of less than 50 amino acid residues, a hinge, CD137 (4-1BB), a transmembrane domain of CD28 and an intracellular signaling domain for CD3 zeta (see entire document, e.g., abstract, pages 1-6, 16, 19, and 25-27 and Figure 1). Jensen teaches that the CAR can further comprise a co-stimulatory domain from CD28 (see page 23). Jensen teaches that almost any molecule that binds a given antigen with high affinity can be used as an antigen-specific targeting region (see pages 5-6 and 18). Jensen teaches engineered T cells comprising such chimeric antigen receptors and compositions comprising such cells and a carrier (see pages 2 and 32 and claim 85). Jensen teaches that the antibodies can be VH single domain antibodies, “if the VH domain alone is sufficient to confer antigen-specificity ("single-domain antibodies"” (see pages 17 and 19). “For example, two or more antigen-specific targeting regions containing immunoglobulin sequences (e.g. scFvs and/or single-domain antibodies) may be linked to each other”, page 19) or bivalent antibodies that bind the same antigen (see pages 18 and 19).
With respect to the disclosed antigen-binding domains or antigen-specific targeting regions Jensen discloses that "Antigen-specific targeting region" (ASTR) as used herein refers to the region of the CAR which targets specific antigens. The CARs of the invention comprise at least two targeting regions which target at least two different antigens. In an embodiment, CARs comprise three or more targeting regions which target at least three or more different antigens. The targeting regions on the CAR are extracellular. In some embodiments, the antigen-specific targeting regions comprise an antibody or a functional equivalent thereof or a fragment thereof or a derivative thereof and each of the targeting regions target a different antigen. The targeting regions may comprise full length heavy chain, Fab fragments, single chain Fv (scFv) fragments, divalent single chain antibodies or diabodies, each of which are specific to the target antigen. There are, however, numerous alternatives, such as linked cytokines (which leads to recognition of cells bearing the cytokine receptor), affibodies, ligand binding domains from naturally occurring receptors, soluble protein/peptide ligand for a receptor (for example on a tumor cell), peptides, and vaccines to prompt an immune response, which may each be used in various embodiments of the invention. In fact, almost any molecule that binds a given antigen with high affinity can be used as an antigen-specific targeting region, as will be appreciated by those of skill in the art.” (see pages 5-6)
One of skill in the art would at once envisage that the antigen-specific targeting regions include different antibodies that bind different epitopes on the same antigen as well as two of the same antigen-specific targeting regions which would then bind the same epitope.
June et al teach that antibodies include VHH camelid antibodies (another form of single domain antibodies) which can be included in a CAR (see page 6).
Accordingly, it would have been prima facie obvious to use VHH camelid antibodies in the bivalent CARs of Jensen and further engineer T cells to comprise such CARs and such T cells in compositions further comprising a carrier. Notably, Jensen et al teach that almost antibody binding domain can be used (which could be in any order as set forth in claims 46-47) including VH domains, and June et al establish that VHH are binding domains that can be used in CARs, such that one of skill would have recognized VHH single domain antibodies as one of a finite, predictable number of binding domains that could be used in the CARs of Jensen. Furthermore, as VHH are smaller than scFv or other antibodies of Jensen, there would also be an advantage of having to make a smaller construct using two VHH which would be easier to produce and express in cells. As these single domain antibodies were also known as antigen-binding domains that could be used in CARs comprising two or more antigen binding domains and methods of making such CARs were known in the art, one of skill in the art would also see that this would be considered combining prior art elements according to known methods to yield predictable results or simple substitution of one known element for another to obtain predictable results.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, absent a showing otherwise.
Claims 44-49, 58-72 and 75-77 are rejected under 35 U.S.C. 103 as being unpatentable over Jensen, Michael (WO 2013/123061 A1, IDS) and June et al (US 2014/0099340 A1, IDS), as applied to claims 44-47, 58-60, 62-72 and 75-77 above and in further view of Armitage et al (US 2014/0161828 A1, IDS).
The above 103 rejection suggests and teaches that which is set forth above.
Armitage et al teach bispecific antibodies that bind BCMA on two different epitopes, including single domain antibodies for treating B cell cancers (see pages 3 and 22-24).
Thus it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to use include two camelid VHH that bind BCMA at the same and/or different epitopes antibodies in the CARs suggested above. Notably, adding VHH antibodies that bind BCMA in bivalent CARs of Jensen, would have the advantage of targeting CAR expressing cells to B cell cancers expressing BCMA to treat the cancer. Here, while the antibody constructs also target cancer, the prior art of Jensen and June et al establish that CAR expressing cells can also be used to treat cancer and have advantages over antibody treatments (see e.g., June et al at page 5). Furthermore, targeting the same and/or different epitopes on BCMA would be understood to increase the avidity of the CAR to better treat the cancer as compared to a monovalent CAR. Notably, the CAR could be bivalent for both different epitopes such that the CAR would be bivalent and bispecific which would be expected to increase avidity and affinity.
Notably, as set forth in the Supreme Court decision in KSR International Co. v. Teleflex Inc. 82 USPQ2d 1385 (2007):
“A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton.”KSR, 82 USPQ2d at 1397. “[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 “the inferences and creative steps that a person of ordinary skill in the art would employ.” KSR, 82 USPQ2d at 1396. An obviousness determination is not the result of a rigid formula disassociated from the consideration of the facts of a case. Indeed, the common sense of those skilled in the art demonstrates why some combinations would have been obvious where others would not. See KSR Int7 Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) ("The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results."). In this case, the combination of VHH that bind to BCMA in the CARs of Jensen, creates constructs that have the combination of known elements according to known methods that would yield predictable results.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, absent a showing otherwise.
In the response, Applicant traverses the rejections and argues that: “i) The presumed prima facie case of obviousness is rebutted by evidence of unexpected results.”
Applicant submits that: “For example, as noted in the present specification, among other advantages, the present bispecific CARs avoid pairing of a heavy chain and a light chain, and thus the problem of misfolding of the extracellular antigen binding domain, as mentioned above, can be reduced in engineered immune cells expressing such CARs (see paragraph [0055] of the present specification).”
Further, as stated in Mr. Zhuang’s Declaration, It is well understood in the field that the structure of the extracellular antigen binding domain of a CAR can significantly impact the functionalities and efficacies of the CAR and a CAR-T cell expressing same. Our studies found that tandem VuH-based CARs not only overcome of misfolding challenges related to the scFv fragment-based CARs but also demonstrated unexpected and surprising cytotoxicity against tumor cells. Paragraph 10 below contains in vitro cytotoxicity studies of various Bi-VHH CARs compared with various bispecific/bivalent CARs comprising scFv antibodies (Bi-scFv CARs) and bispecific CARs comprising VH antibodies (Bi-VH CARs). The in vitro cytotoxicity studies contain two parts, namely Parts A and B. Part A contains two groups of experiments: Group I compares anti-tumor effect of bispecific BCMA x CD19 VuH CARs to that of bispecific BCMA x CD19 scFv and VH CARs in K562.BCMA.Luc and Nalm6.Luc target tumor cells; Group II compares anti-tumor effect of bispecific CD19 x CD20 VuH CARs to that of bispecific CD19 x CD20 scFv and VH CARs in K562- CD19.Luc and K562-CD20.Luc target tumor cells. Part B contains one group of experiments comparing anti-tumor effect of bivalent BCMA VuH CARs to that of bivalent BCMA scFv CARs in RPMI8226.Luc target tumor cells. All tested CARs had identical hinge, transmembrane and cytoplasmic domains. In each group of comparative experiments, identical experimental conditions were used. To demonstrate that any observed effect is not dependent on the antibody sequence or the way in which the CAR is constructed, the tested CARs covered a large variety of antibody sequences and were constructed with the two antibodies in different orders (i.c., a first antibody located at the N-terminus or C-terminus of a second antibody). All experiments clearly and consistently demonstrate that the claimed Bi-VaH CARs exhibit significantly higher cytotoxicity when compared to Bi-scFv or Bi-VH CARs, regardless of the antibody sequences used or how the CARs were constructed. The superior anti-tumor effect which is generally observed for the claimed CAR structure is truly unexpected. In my opinion, it would not be possible, let alone obvious, to predict, without experimentation, that the claimed Bi-VaH CARs would exhibit significantly higher cytotoxicity when compared to Bi-scFv or Bi-VH CARs. Our studies as submitted above further evidence the superiority of the claimed CAR structure having two VuH domains in tandem in the extracellular antigen binding domains. Paragraphs 7, 9, and 11 of Mr. Zhuang’s Declaration.”
In response, while the declaration and arguments were fully considered and weighed in the consideration of the outstanding 103 rejections (see MPEP 716.02(c), the declaration and arguments were not considered sufficient to obviate the 103 rejections for the following reasons:
scFv, VH and VHH were known in the art to have different structures and antigen binding properties such that one of skill in the art recognized there were advantages and disadvantages to each, while the prior art recognized that any antigen binding region could be used as binding domains in a CAR. Notably, it was known that VHH did not require pairing of a heavy chain and a light chain, and thus the problem of misfolding of the extracellular antigen binding domain would not be present and affinities affect cytotoxicity of CAR antibodies such that higher cytotoxicity alone is insufficient to establish unexpected results.
As set forth below, Gschwind et al teach bispecific antibody comprising two VHH camelid antibodies (see abstract). Gschwind et al teach that VHH camelid antibodies have the advantages of
“• only a single domain is required to bind an antigen with high affinity and with
high selectivity, so that there is no need to have two separate domains
present, nor to assure that these two domains are present in the right spacial
conformation and configuration (i.e. through the use of especially designed
linkers, as with scFv's);
• immunoglobulin single variable domains can be expressed from a single
nucleic acid molecule and do not require any post-translational modification
(like glycosylation;
• immunoglobulin single variable domains can easily be engineered into
multivalent and multispecific formats (as further discussed herein);
• immunoglobulin single variable domains have high specificity and affinity for
their target, low inherent toxicity and can be administered via alternative routes
than infusion or injection;
• immunoglobulin single variable domains are highly stable to heat, pH,
proteases and other denaturing agents or conditions and, thus, may be
prepared, stored or transported without the use of refrigeration equipments;
• immunoglobulin single variable domains are easy and relatively inexpensive to
prepare, both on small scale and on a manufacturing scale. For example,
immunoglobulin single variable domains can be produced using microbial
fermentation (e.g. as further described below) and do not require the use of
mammalian expression systems, as with for example conventional antibodies;
• immunoglobulin single variable domains are relatively small (approximately
15 kDa, or 10 times smaller than a conventional lgG) compared to
conventional 4-chain antibodies and antigen-binding fragments thereof, and
therefore show high(er) penetration into tissues (including but not limited to
solid tumors and other dense tissues) and can be administered in higher
doses than such conventional 4-chain antibodies and antigen-binding
fragments thereof;
• VHHs have specific so-called "cavity-binding properties" (inter alia due to their
extended CDR3 loop, compared to V H domains from 4-chain antibodies) and
can therefore also access targets and epitopes not accessible to conventional
4-chain antibodies and antigen-binding fragments thereof;
• VHHs have the particular advantage that they are highly soluble and very
stable and do not have a tendency to aggregate (as with the mouse-derived
antigen-binding domains”
Therefore, the data presented is insufficient to establish unexpected results in this case that are sufficient to obviate the outstanding 103 rejection.
Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." (see MPEP 716.02 (d)).
In the instant case, the data presented are for specific bispecific VHH CAR constructs with specific transmembrane domains and intracellular signaling domains, while the claims encompass any VHH CAR constructs that bind any antigen and with any transmembrane domain and intracellular signaling domain such that the data presented is clearly not commensurate in scope with the claims. Notably, the data presented only provides CAR data that binds to CD19 and BCMA or CD19 and CD20, while the elected species of bispecific VHH CAR contains a first VHH that binds BCMA AND a second VHH that binds BCMA. Applicant submits that “the extracellular antigen binding domain of a CAR can significantly impact the functionalities and efficacies of the CAR” such that it cannot be determined how bispecific CARs that bind two distinct antigens might be commensurate with bispecific CARs that bind two different epitopes on the same antigen. Furthermore, as “the extracellular antigen binding domain of a CAR can significantly impact the functionalities and efficacies of the CAR” it cannot be determined how the data presented might be commensurate with bispecific CARs that bind different antigens.
Applicant submits that the data presented is commensurate in scope and demonstrates a practicable advantage to the claimed structure because “Mr. Zhuang’s declaration presents data showing that certain exemplary Bi- VHH CARs exhibit superior cytotoxicity compared to Bi-scFv and Bi-VH CARs, Applicant submits that the data support that the claimed structure itself confers a generalizable advantage—namely, the ability to avoid misfolding and to achieve higher activity in a variety of contexts.
In response, the scFv, VHH, and VH used in the experiments where never characterized for stability, affinity or aggregation properties, and different VHH antibodies will have different stability, affinity or aggregation properties that may be responsible for the higher cytotoxicity of the Bi-VHH-CARs.
As set forth above, VHH are known to have advantages over scFv or VH fragments such that the datacannot be commensurate in scope with the claims which the evidence is offered to support because the advantages would be expected so it cannot be said there are unexpected results.
Different results obtained from different constructs does not necessarily mean the results are unexpected.
Applicant has previously submitted that “the extracellular antigen binding domain of a CAR can significantly impact the functionalities and efficacies of the CAR” such that one of skill in the art would expect that scFv and VHH binding domains would have different functionalities and efficacies when used in a CAR. Thousands of distinct VHH antibodies and scFv antibodies can made that bind BCMA, CD19 or CD20 and each different “antibody” would have different functionalities and efficacies when used in a CAR as admitted by Applicant, so comparing a VHH CAR to an scFv CAR, which have different binding domains, cannot be said to have practical significance (see MPEP 716.02(b). Notably, the declaration also establishes that the bispecific scFv BCMA and CD19 CAR A001 displays similar cytotoxicity to the bispecific VHH BCMA and CD19 CAR A019 at an E:T ratio of 10:1, such that it is apparent CARs comprising scFvs can functions similarily to CARs comprising a VHH depending on the binding domain and assay used. Overall the data presented does not present a basis for judging the practical significance of the data because “the extracellular antigen binding domain of a CAR can significantly impact the functionalities and efficacies of the CAR”.
Applicant further submits “ii) Jensen is directed to scFv based bispecific CARs and provides no motivation to depart from scFv antigen binding domains.”
In response, this argument was not found persuasive because Jensen discloses that any molecule with high affinity can be used as an ASTR in a bispecific antibody construct of Figure 1.
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Jensen further discloses that "Antigen-specific targeting region" (ASTR) as used herein refers to the region of the CAR which targets specific antigens. The CARs of the invention comprise at least two targeting regions which target at least two different antigens. In an embodiment, CARs comprise three or more targeting regions which target at least three or more different antigens. The targeting regions on the CAR are extracellular. In some embodiments, the antigen-specific targeting regions comprise an antibody or a functional equivalent thereof or a fragment thereof or a derivative thereof and each of the targeting regions target a different antigen. The targeting regions may comprise full length heavy chain, Fab fragments, single chain Fv (scFv) fragments, divalent single chain antibodies or diabodies, each of which are specific to the target antigen. There are, however, numerous alternatives, such as linked cytokines (which leads to recognition of cells bearing the cytokine receptor), affibodies, ligand binding domains from naturally occurring receptors, soluble protein/peptide ligand for a receptor (for example on a tumor cell), peptides, and vaccines to prompt an immune response, which may each be used in various embodiments of the invention. In fact, almost any molecule that binds a given antigen with high affinity can be used as an antigen-specific targeting region, as will be appreciated by those of skill in the art.” (see pages 5-6, emphasis added)
Accordingly, Jensen is not limited to scFv or VH binding domains and provides motivation to use any other ASTR known in the art.
Applicant further submits “iii) One of ordinary skill in the art would not have a reasonable expectation of success in combining the references to arrive at the presently claimed bispecific CAR.”
Applicant further submits that “The Examiner maintains that one of ordinary skill would have recognized the advantages of VHH domains. The Examiner asserts that “as VHH are smaller than the other antibodies of Jensen, there would also be an advantage of having to make a smaller construct using two VaH which would be easier to produce and express in cells” (Office Action, page 6). The Examiner further asserts that that “[o]ne of skill in the art also recognized that a VHH does not require a VL for pairing as pointed out in the argument”. Regarding the issue of misfolding, the Examiner alleges that “it is noted that the art previously recognized that some bispecific antibody formats suffer from the major problem of mispairing because pairing of noncognate heavy and light chains results in inactive antigen-binding sites (Holliger er al (Nature Biotechnology, 23(9):1126-1136, 2005, see page 1132), and that VHH have significant advantages such as not requiring have two antibody domains (VL and VH) in the right special conformation and configuration as with scFvs and VHH have the particular advantage that they are highly soluble and very stable and do not have a tendency to aggregate (as with the mouse derived antigen- binding domains (see WO 2012/131076 Al, Gschwind et al, pages 11 and 12)”. Id.
However, the mere recognition of certain properties of VHH domains in the antibody field does not provide a teaching or motivation to construct a bispecific CAR with two VHH domains in tandem. Indeed, the Examiner’s argument conflates alleged general knowledge regarding VHH domains as motivation to use them in the specific context of tandem VHH -based bispecific CARs. The cited art does simply does not provide any expectation of success for such a construct.
As previously presented, Jensen does not provide the skilled person with any reasonable expectation of providing an improved CAR by replacing the scFv antigen binders with VHH sdAbs. In fact, Jensen does not disclose or even recognize the potential advantages provided by the specific CAR structure as claimed—two tandem VHH domains in the extracellular domain. As discussed above, without knowing such advantages provided by tandem VHH based bispecific CARs, those skilled in the art would have had no reasons to randomly pick and choose various passages from different documents cited by the Examiner to arrive at the present claims, much less so with a reasonable expectation of success.”
In response, this argument was not found persuasive because Jensen discloses that any molecule with high affinity can be used as an ASTR. Jensen need not disclose or even recognize the potential advantages of two tandem VHH domains in the extracellular domain. If Jensen disclosed or recognized the potential advantages of two tandem VHH domains in the extracellular domain, the rejection would have been a 102 rejection or a single reference 103 rejection. Here, VHH were known in the art as molecules with high affinity that can bind antigens, as evidenced by June and many others, such that there is a clear reasonable expectation of success in using two VHH in bispecific CAR constructs.
Applicant further submits “iv) The Office impermissibly applies hindsight bias.”
Applicant submits that “If the use of tandem VHH domains in bispecific or bivalent CAR constructs was obvious in view of the longstanding availability of VHH antibodies and the well-recognized challenges in CAR-T cell engineering—such as misfolding due to heavy and light chain pairing (which it is not) —then it is reasonable to ask why those skilled in the art had not already implemented the claimed solution.”
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In this case, this argument is not found persuasive because June et al teach that antibodies include VHH camelid antibodies can be included in a CAR and the rejection takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made. In a 103 rejection, the prior art does not anticipate the rejection so in any 103 rejection one skilled in the art had not already implemented the claimed solution. Applicant appears to desire a standard for patentably where no claims would be considered obvious in view of the prior art, which is not the current standard (see MPEP § 2143).
Then with respect to the second 103 rejection Applicant submits that “Armitage fails to make up for the above-discussed deficiencies of Jensen and June” with regard to claim 44.
In response, the arguments with respect to Jensen and June with respect to claim 44 were not found persuasive and Armitage was cited with respect to the BCMA limitations of dependent claims that are encompassed by claim 44. As Applicant did not specifically argue the rejection of the BCMA dependent claims, this rejection is maintained for the reasons of record.
Therefore, after careful and complete consideration of Applicant’s response and the record as a whole, for these reasons and the reasons set forth in the previous office action, these rejections are being maintained.
Claims 44-47, 58-60, 62-72 and 75-77 are rejected under 35 U.S.C. 103 as being unpatentable over Loew et al (WO 2015/142675 A2), Jamnani et al (Biochimica et Biophysica Acta 1840:378-387, 2013) and Gschwind et al (WO 2012/131076 A1).
With respect to the claims, Loew teaches chimeric antigen receptors (CAR) comprising, in the following order, a signal sequence, 2 or more antibodies or other antigen-binding domains linked together with a peptide linker of less than 50 amino acid residues, a hinge, CD137 (4-1BB), a transmembrane domain of CD28 and an intracellular signaling domain for CD3 zeta (see entire document, e.g., abstract, pages 1-6, 55-56, 69-70, 106-110, 150 and 231). Loew teaches that the CAR can further comprise a co-stimulatory domain from CD28 (see page 36). Loew teaches that almost any molecule that binds a given antigen with high affinity can be used as an antigen-specific targeting region, in a bispecific CAR including VHH (see pages 55-56 and 125-126). Loew teaches engineered T cells comprising such chimeric antigen receptors and compositions comprising such cells and a carrier (see pages 63, 88 and 247). Loew teaches that the antibodies in the bispecific CARs can bind the same antigen at the same or different epitope or different antigen(see pages 106-110).
Jamnani et al teach a CAR comprising a VHH camelid antibody (see abstract).
Gschwind et al teach bispecific antibody comprising two VHH camelid antibodies (see abstract). Gschwind et al teach that VHH camelid antibodies have the advantages of
“• only a single domain is required to bind an antigen with high affinity and with
high selectivity, so that there is no need to have two separate domains
present, nor to assure that these two domains are present in the right spacial
conformation and configuration (i.e. through the use of especially designed
linkers, as with scFv's);
• immunoglobulin single variable domains can be expressed from a single
nucleic acid molecule and do not require any post-translational modification
(like glycosylation;
• immunoglobulin single variable domains can easily be engineered into
multivalent and multispecific formats (as further discussed herein);
• immunoglobulin single variable domains have high specificity and affinity for
their target, low inherent toxicity and can be administered via alternative routes
than infusion or injection;
• immunoglobulin single variable domains are highly stable to heat, pH,
proteases and other denaturing agents or conditions and, thus, may be
prepared, stored or transported without the use of refrigeration equipments;
• immunoglobulin single variable domains are easy and relatively inexpensive to
prepare, both on small scale and on a manufacturing scale. For example,
immunoglobulin single variable domains can be produced using microbial
fermentation (e.g. as further described below) and do not require the use of
mammalian expression systems, as with for example conventional antibodies;
• immunoglobulin single variable domains are relatively small (approximately
15 kDa, or 10 times smaller than a conventional lgG) compared to
conventional 4-chain antibodies and antigen-binding fragments thereof, and
therefore show high(er) penetration into tissues (including but not limited to
solid tumors and other dense tissues) and can be administered in higher
doses than such conventional 4-chain antibodies and antigen-binding
fragments thereof;
• VHHs have specific so-called "cavity-binding properties" (inter alia due to their
extended CDR3 loop, compared to V H domains from 4-chain antibodies) and
can therefore also access targets and epitopes not accessible to conventional
4-chain antibodies and antigen-binding fragments thereof;
• VHHs have the particular advantage that they are highly soluble and very
stable and do not have a tendency to aggregate (as with the mouse-derived
antigen-binding domains”
(see pages 11-12).
Accordingly, it would have been prima facie obvious to use VHH camelid antibodies in the bispecific CARs of Loew and further engineer T cells to comprise such CARs and such T cells in compositions further comprising a carrier. Notably, Loew teach that VHH domains can be used in bispecific CARs, Jamnani et al make a VHH-CAR and Gschwind et al teach nine advantages of VHH camelid antibodies, such that one of skill would have recognized VHH single domain antibodies having these advantages in bispecific CARs and used two VHH domains in bispecific CARs. As these single domain antibodies were also known as antigen-binding domains that could be used in CARs comprising two or more antigen binding domains and methods of making such CARs were known in the art, one of skill in the art would also see that this would be considered combining prior art elements according to known methods to yield predictable results or simple substitution of one known element for another to obtain predictable results and would have reasonably expected success in making such constructs.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, absent a showing otherwise.
Claims 44-49, 58-72 and 75-77 are rejected under 35 U.S.C. 103 as being unpatentable over Loew et al (WO 2015/142675 A2), Jamnani et al (Biochimica et Biophysica Acta 1840:378-387, 2013) and Gschwind et al (WO 2012/131076 A1), as applied to claims 44-47, 58-60, 62-72 and 75-77 above and in further view of Armitage et al (US 2014/0161828 A1, IDS).
The above 103 rejection suggests and teaches that which is set forth above.
Armitage et al teach bispecific antibodies that bind BCMA on two different epitopes, including single domain antibodies for treating B cell cancers (see pages 3 and 22-24).
Thus it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to use include two camelid VHH that bind BCMA at the same and/or different epitopes antibodies in the CARs suggested above. Notably, adding VHH antibodies that bind BCMA in bispecific CARs suggested above, would have the advantage of targeting CAR expressing cells to B cell cancers expressing BCMA to treat the cancer. Furthermore, targeting the same and/or different epitopes on BCMA would be understood to increase the avidity of the CAR to better treat the cancer as compared to a monovalent CAR. Notably, the CAR could be bivalent for both different epitopes such that the CAR would be bivalent and bispecific which would be expected to increase avidity and affinity.
Notably, as set forth in the Supreme Court decision in KSR International Co. v. Teleflex Inc. 82 USPQ2d 1385 (2007):
“A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton.”KSR, 82 USPQ2d at 1397. “[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 “the inferences and creative steps that a person of ordinary skill in the art would employ.” KSR, 82 USPQ2d at 1396. An obviousness determination is not the result of a rigid formula disassociated from the consideration of the facts of a case. Indeed, the common sense of those skilled in the art demonstrates why some combinations would have been obvious where others would not. See KSR Int7 Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) ("The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results."). In this case, the combination of VHH that bind to BCMA in the CARs suggested above, creates constructs that have the combination of known elements according to known methods that would yield predictable results.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, absent a showing otherwise.
In the response, Applicant traverses the rejections and argues that: “Loew does not, in fact, teach a CAR with “2 or more antibodies or other antigen-binding domains”, contrary to the Examiner’s assertion. Instead, Loew describes the co-expression of two separate, different chimeric antigen receptors on the surface of a single immune effector cell, rather than a single CAR molecule comprising two antigen binding domains within its extracellular region.”
In response, Loew is prior art for all it discloses, Loew discloses CAR with 2 or more antibodies or other antigen-binding domains (see entire document, e.g., abstract, pages 1-6, 55-56, 69-70, 106-110, 150 and 231). Loew discloses that the binding domains or antibodies included in the CAR can be bispecific antibodies or multispecific antibodies at ¶ 250
As used herein, the term "binding domain" or "antibody molecule" refers to a
protein, e.g., an immunoglobulin chain or fragment thereof, comprising at least one
immunoglobulin variable domain sequence. The term "binding domain" or "antibody
molecule" encompasses antibodies and antibody fragments. In an embodiment, an antibody
molecule is a multispecific antibody molecule, e.g., it comprises a plurality of
immunoglobulin variable domain sequences, wherein a first immunoglobulin variable
domain sequence of the plurality has binding specificity for a first epitope and a second
immunoglobulin variable domain sequence of the plurality has binding specificity for a
second epitope. In an embodiment, a multispecific antibody molecule is a bispecific
antibody molecule. A bispecific antibody has specificity for no more than two antigens. A
bispecific antibody molecule is characterized by a first immunoglobulin variable domain
sequence which has binding specificity for a first epitope and a second immunoglobulin
variable domain sequence that has binding specificity for a second epitope.
Loew discloses at ¶¶ 455-456
Bispecific CARs
In an embodiment a multispecific antibody molecule is a bispecific antibody
molecule. A bispecific antibody has specificity for no more than two antigens. A bispecific
antibody molecule is characterized by a first immunoglobulin variable domain sequence
which has binding specificity for a first epitope and a second immunoglobulin variable
domain sequence that has binding specificity for a second epitope. In an embodiment the
first and second epitopes are on the same antigen, e.g., the same protein (or subunit of a
multimeric protein).
Therefore, it is apparent that Loew does disclose bispecific CARs comprising two antigen binding domains.
Applicant further argues that “Jamnani is not concerned with CARs that incorporate two VHH antigen binding domains. Instead, Jamnani reports the preparation of a series of CARs containing only a single VHH that targeted HER2.”
In response, Jamnani is not relied on for CARs that incorporate two VHH. Here the claimed invention is obvious because Loew teaches that VHH domains can be used in bispecific CARs, Jamnani et al make a VHH-CAR and Gschwind et al teach nine advantages of VHH camelid antibodies, such that one of skill would have recognized VHH single domain antibodies having these advantages in bispecific CARs used two VHH domains in bispecific CARs in view of the art as a whole.
Additional advantages of bispecific VHH antibodies are disclosed in Conrath et al (JBC, 276(10):7346-7350, 2001). Conrath et al discloses that “bispecific and bivalent constructs based on camel single-domain antibody fragments makes them particularly attractive for use in therapeutic or diagnostic programs” and that “the expression levels, ease of purification, and the solubility of the recombinant proteins were comparable with those of the constituent monomers”, such that one would recognize that bispecific VHH would be reasonably expected to be functional in CARs just like a VHH is functional in monospecific single VHH-CARs.
Then with respect to the second 103 rejection Applicant submits that “Armitage fails to make up for the above-discussed deficiencies of Loew, Jamnani, and Gschwind ” with regard to claim 44.
In response, the arguments with respect to Jensen and June with respect to claim 44 were not found persuasive and Armitage was cited with respect to the BCMA limitations of dependent claims that are encompassed by claim 44. As Applicant did not specifically argue the rejection of the BCMA dependent claims, this rejection is maintained for the reasons of record.
Therefore, after careful and complete consideration of Applicant’s response and the record as a whole, for these reasons and the reasons set forth in the previous office action, these rejections are being maintained.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory obviousness-type double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the conflicting application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement.
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
Claims 44-49, 58-72 and 75-77 are rejected on the grounds of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-24 of US Patent 10,934,363, IDS. Although the conflicting claims are not identical, they are not patentably distinct from each other for the following reasons:
The claims of US Patent 10,934,363 recite:
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Accordingly, the subject matter claimed in the instant application is anticipated by the subject matter claimed in the patent.
Claims 44-49, 58-72 and 75-77 are rejected on the grounds of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-21 of US Patent 11,186,647, IDS. Although the conflicting claims are not identical, they are not patentably distinct from each other for the following reasons:
The claims of US Patent 11,186,647 recite:
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Accordingly, the subject matter claimed in the instant application is anticipated by the subject matter claimed in the patent.
Claims 44-49, 58-72 and 75-77 are rejected on the grounds of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-26 of US Patent 11,535,677, IDS in view of Jensen, Michael (WO 2013/123061 A1, IDS), June et al (US 2014/0099340 A1, IDS) and Armitage et al (US 2014/0161828 A1, IDS). Although the conflicting claims are not identical, they are not patentably distinct from each other for the following reasons:
The claims of US Patent 11,535,677 recite:
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With respect to the claims, Jensen teaches chimeric antigen receptors (CAR) comprising, in the following order, a signal sequence, 2 or more antibodies or other antigen-binding domains linked together with a peptide linker of less than 50 amino acid residues, a hinge, CD137 (4-1BB), a transmembrane domain of CD28 and an intracellular signaling domain for CD3 zeta (see entire document, e.g., abstract, pages 1-5, 16, 19, and 25-27). Jensen teaches that the CAR can further comprise a co-stimulatory domain from CD28 (see page 23). Jensen teaches that almost any molecule that binds a given antigen with high affinity can be used as an antigen-specific targeting region (see pages 5 and 18). Jensen teaches engineered T cells comprising such chimeric antigen receptors and compositions comprising such cells and a carrier (see pages 2 and 32 and claim 85). Jensen teaches that the antibodies can be VH single domain antibodies (see page 17) or bivalent antibodies that bind the same antigen (see pages 18 and 19) and one of skill in the art would at once envisage that the antibodies include different antibodies that bind different epitopes on the same antigen as well as two of the same antibodies which would then bind the same epitope.
June et al teach that antibodies include VHH camelid antibodies (single domain antibodies) which can be included in a CAR (see page 6).
Armitage et al teach bispecific antibodies that bind BCMA on two different epitopes, including single domain antibodies for treating B cell cancers (see pages 3 and 22-24).
Thus it would have been obvious to one of ordinary skill in the art at the time the invention was made to modify the claimed bispecific 2-VHH CARs to include any additional structures from the CARs as taught by Jensen, June and Armitage. Notably, as evidenced by the art these additional structures are all commonly included in CAR constructs, T cells engineered to express said CAR and in compositions comprising said cells because this would be seen as combining prior art elements according to known methods to yield predictable results.
Accordingly, the subject matter claimed in the instant application would be seen as an obvious variation of the subject matter claimed in the patent.
In the response, Applicant requests that the double patenting rejections be held in abeyance.
In response the rejections will be maintained until appropriately resolved.
Conclusion
No claims are allowed. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. WO 2016/090034 A2 (Brogdon et al ) discloses CARs comprising VHH domains and CARs comprising bispecific antibodies (see pages 23-27).
THIS ACTION IS MADE FINAL. 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.
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 works a flexible schedule.
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
November 21, 2025