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 .
Application Status
Claims 1-12, 14, 20, 23-24, 28, 32, 35, 38, 40, 47, 59, 62, 65-66, and 82 are pending and examined on the merits herein.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on pages 43-44. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the term Alexa™ Fluor on page 40 and a number of clinical agents such as Keytruda® and Opdivo® on page 95, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 82 is objected to because of the following informalities:
Claim 82 recites “A human NK cells transduced” should read: Human NK cells transduced.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 5-6, 10-11, 14, 20, 23-24, 28, 32, 35, and 38 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.
Claims 5-6, 10-11, 14, 20, 23-24, 28, 32, and 38 all recite structures or sequences with a limitation of “or an equivalent thereof” which renders these claims indefinite as the ordinary artisan would be unable to determine what qualifies as an “equivalent.” Instant specification defined equivalent of an antibody to a peptide, antibody fragment, antibody variant, antibody derivative and antibody mimetic that bind to the same epitope as the reference antibody (paragraph 0093). The instant specification also defined the term "biological equivalent thereof' is intended to be synonymous with "equivalent thereof' when referring to a reference protein, antibody, polypeptide or nucleic acid, intends those having minimal homology while still maintaining desired structure or functionality (paragraph 0097).
Regarding claims 5, 10, it is unclear what epitopes scFVs comprising a SEQ ID NO:32 OR SEQ ID NO:33 are binding to determine the equivalent of a VL comprising SEQ ID NO:32, and the equivalent of a VH comprising SEQ ID NO:33. Regarding claims 10-11, 14, 20, 23-24, and 38, it is unclear what epitopes scFVs comprising the recited sequences binds to determine the equivalent of the recited sequences.
Regarding claims 14, 20, 24, 32, and 38, it is unclear what protein or polypeptide has minimal homology while still maintaining desired structure or functionality of the recited sequences.
Thus, the metes and bounds of the claims are unclear.
Claim 35 depends from claim 32 and is therefore included in this rejection.
Further regarding claim 35, options 2-6 recite “the fifth nucleotide sequence encoding the self-cleaving peptide located,” the statement is incomplete in that it does not specify the location which renders the claim indefinite.
Claim 35 options 2-6, recite the limitation "the fifth nucleotide sequence" in line 3. There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph 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 the first paragraph of pre-AIA 35 U.S.C. 112:
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 2-3, 7-8, and 23 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. This is a written description rejection.
The teachings of the specification and the claimed invention:
Regarding claim 2: The nature and scope of the claimed invention at issue is a subgenus of antibodies that bind to PSCA defined by a partial structure, an scFv comprised of HCDRs comprising DYYI, WIDPENGDTEFVPKFQG, and GGF (all portions of SEQ ID NO: 33).
Regarding claim 3: The nature and scope of the claimed invention at issue is a subgenus of antibodies that bind to PSCA defined by a partial structure, an scFv comprised of LCDRs comprising SASSSVRFIH, DTSKLAS, and QQWGSSPFT ( all portions of SEQ ID NO: 32).
Regarding claim 7: The nature and scope of the claimed invention at issue is a subgenus of antibodies that bind to PSCA defined by a partial structure, an scFv comprised of HCDRs comprising SYSMS, YINDSGGSTFYPDTVKG, and RMYYGNSHWHFDV (all portions of SEQ ID NO: 35).
Regarding claim 8: The nature and scope of the claimed invention at issue is a subgenus of antibodies that bind to PSCA defined by a partial structure, an scFv comprised of LCDRs comprising GTSQDINNYLN, YTSRLHS, and QQSKTLPWT ( all portions of SEQ ID NO: 34).
Regarding claim 23: The nature and scope of the claimed invention at issue is a subgenus of CARs with a binding moiety to PSCA, comprising an amino acid sequence at with 1-5 amino acid modifications to SEQ ID NO: 1, 40, 41 or 42 which would permit changes to the CDRs.
The instant specification discloses that the CDRs are primarily responsible for binding to an epitope of an antigen. The CD Rs of each chain are typically referred to as CDR1, CDR2, and CDR3, numbered sequentially starting from the N-terminus, and are also typically identified by the chain in which the particular CDR is located (heavy chain regions labeled CDHR and light chain regions labeled CDLR). Thus, a CDHR3 is the CDR3 from the variable domain of the heavy chain of the antibody in which it is found, whereas a CDLR1 is the CDR1 from the variable domain of the light chain of the antibody in which it is found. For example, a PSCA antibody will have a specific VH region and the VL region sequence unique to the PSCA relevant antigen, and thus specific CDR sequences. (paragraph 0093). The instant specification further discloses that a single-chain variable fragment, also referred to herein as a fragment of an antibody, and is a fusion protein of the variable regions of the heavy (VH) and light chains (VL) of immunoglobulins, optionally connected with a short linker peptide of about 10 to about 25 amino acids (paragraph 0095). There are no examples of a single domain antibody in the instant specification or demonstration of binding after chain swapping with the recited SEQ ID NOs.
The instant specification does not define the structural features of the paratope-epitope binding and the residues therein that facilitate binding of an antibody to a PSCA moiety or an infectious disease targeting moiety. The instant specification discloses 4 scFv comprising 2 separate sets of 6 CDRs (pages 57-58). Figure 2 additionally discloses that the PSCA-scFv comprises VL-L-VH or VH-L-VL. Epitope mapping was not done for any of the clones. The instant specification has not disclosed the structural features or amino acid sequences of a representative subgenus of antibodies comprising 1-5 residue modifications to the recited SEQ ID NOs.
Claim Analysis:
Regarding claim 2-3 and 7-8: A skilled artisan would recognize that the specificity of an antibody is dependent upon six specific CDR sequences and different combinations of CDR sequences greatly alter antigen binding. The instant specification has not disclosed the structural features or amino acid sequences of a representative subgenus of antibodies comprising a single chain comprising one of SEQ ID NO: 32-35 that have the ability to bind to PSCA. Therefore, a claim directed to at least one light or heavy chain sequence, would not permit a skilled artisan to envision the subgenus of antibodies comprising such sequences and have the ability to bind PSCA as claimed.
Regarding claim 23: As detailed below, absent empirical determination, one skilled in the art would be unable to predict or envision which residues of the heavy and light chain CDRs of claim 23 may be changed to such that 1-5 amino acid modifications have been made, such that the resultant variant CDR residues form an antigen-binding site capable of binding PSCA.
State of the Art
It is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs (or hypervariable regions), which provide structure of the antigen binding site and the majority of the contact residues for the binding of the antibody to its target epitope (Almagro & Fransson, Frontiers in Bioscience 2008; 13:1619-33; entire document, specifically note Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). Through analysis of different methods for humanizing antibodies, Almagro et al. shows that all of the CDRs of the heavy and light chain, in their proper order of CDR1, then 2, then 3, and in the context of framework sequences which maintain their required conformation are generally required to produce a humanized antibody in which the heavy and light chains associate to form an antigen-binding region that binds the same antigen as the parental rodent antibody (entire document, specifically note “Section 4”).
Examples of antigen binding domains comprising only a VH (or less commonly, a VL) that in turn comprise only three CDRs certainly do exist in the literature, but those antibodies generally comprise unique structures such as CDR1 and CDR3’s that are elongated in length and that are often disulfide linked such as in heavy chain antibodies (De Genst et al., Developmental and Comparative Immunology, 2006, 30:187-98; entire document, specifically note “1. Introduction” and figure 1 in particular). Further, specific autonomous VH domains that can bind to antigens have also been described in the arts. Ward et al. (Nature, 1989, 341:544-546) teaches that the complete VH domains of several antibodies maintained the ability, although with reduced affinity than the VH-VL, to bind to lysozyme even when they are not paired with the corresponding VL domains (page 545, left column, 2nd complete paragraph; Table 1). Ward et al. also teaches that the autonomous VH domain lacks the binding cavity which is formed when paired with the VL domain (page 546, left column, lines 4-6). Ward et al. further teaches that the VH domain alone is very sticky and contributes to non-specific binding (page 546, left column, last paragraph). Barthelemy et al. (Journal of Biological Chemistry, 2008, 283:3639-3654) analyzed numerus autonomous VH domains that are isolated from a phage display screen that are conducive for producing single domain VH antibodies. Barthelemy et al. showed that several changes in the key residues in the VH framework region that mediates binding with the VL domain are required for stabilization of the autonomous VH domain antibodies (abstract; figure 1A and table 1). These findings further illustrates that residues in the VH framework region are required to stabilize a VH domain to form a functional antigen binding pocket and only some VH domains can function alone to bind to antigens. Furthermore, due to their increase in nonspecific binding, autonomous VH domains have not been shown to be functional in vivo to treat diseases.
Crystallization analysis of different antibody structures when unbound and bound to an antigen shows that the antigen binding domain adapts different confirmations when bound to an antigen (Choi et al., 2011, Molecular BioSystems, 2011, 7:3327-334; specifically page 3327, 1st and 2nd paragraphs in particular). Furthermore, the HV-CDR3 domain is highly variable (Choi et al., page 3327, right column, 1st full paragraph). Although greatly improved, a definitive computational method to accurately predict the structure of the antigen binding site when only analyzing just the CDR3 sequence or an “equivalent therefore” remains to be established (Choi et al., see “abstract”). Thus, a disclosure of a single CDR sequence is not sufficient to determine the antigen binding domain of an antibody because the other CDR sequences provide structure to the antigen binding domain.
Screening phage display libraries comprising human scFv have been used to isolate human antibodies that bind to a specific antigen. Griffiths et al. (The EMBO Journal, 1993, 12:725-734) teaches screening a phage display library with 2.9X107 clones of human scFv to identify the scFv for binding to different antigens (entire document, specifically page 732, see “Selection of phage library” and “screening and sequencing of clones”). One scFv is isolated to bind to MUC1, one scFv is isolated to bind to CEA, and seven different scFVs are isolated from the library to bind to TNFα (entire document, specifically note Table on page 726). This highlights one cannot simply predict which of the scFv out of the 2.9X107 scFv clones would bind to the specific antigen. Also, the phage library that is used for the screen can generate different antibodies.
Guide phage display screening of phages expressing 1.8X108 human scFv clones has been used to identity the five human CDR sequences that function with a heavy chain CDR3 sequence (Klimka et al., British Journal of Cancer, 2000, 83:252-260; page 252, left column). By performing multiple rounds of phage display using complex random pairing of human heavy variable domain with CDR1 and CDR2 sequences with the mouse HV-CDR3 and the light variable region (which has 3 CDR sequences, thus 4 CDR sequences are used in the screen), Klimka et al. identify the human heavy chain CDR1 and CDR2 sequences that can function with the mouse HV-CDR3 and light chain sequences. The identified heavy chain is then used to screen for a human light variable regions (entire document, page 259, left column, 1st full paragraph in particular). Only through a complex screen as taught by Klimka et al. is a skilled artisan able to randomly identify the remaining CDR sequences. Furthermore, similar to the phage display screening for antibodies described above, the CDR sequences that are identified to function with a particular HV-CDR3 sequence is dependent on the particular human antibody library that is used.
Guide phage display screening of phages expressing Fab was performed to isolate a human antibody that displayed similar binding properties as the parental antibody in Beiboer et al. (Journal of Molecular Biology, 2000, 296:833-849). In Beiboer et al, a disclosed variable heavy chain was mixed with a library of 108 light chain sequences and 2x107 light chain sequences to generate Fab libraries in, specifically page 834, see “Humanisation of the light chain”). Following 4 rounds of high stringent antigen selection, seven light chains were obtained (Table 2). The best binding light chain is then shuffled with a library of 1.2x107 human VH comprising the VH-CDR3 of the parent mouse antibody to obtain a Fab human antibody library (page 835, see “Humanisation of the heavy chain”). Following several rounds of screening, one high binding human antibody that maintains the VH-CDR3 sequence of the original parent mouse antibody is obtained that displayed similar binding properties as the parent antibody (abstract; page 835-837, bridging paragraph). Structural modeling of the parent mouse antibody with the selected human antibody showed that the selected human VL sequences are distinct from the parent mouse VL sequence and with each other demonstrating that the VH plays a dominant role in antigen binding (page 834-839, right column, bridging paragraph). Further, structural modeling further showed minimal structural conservation is observed in the CDRs of the human VH (which contains the same CDR3 sequence as the parent mouse antibody) with the parent mouse antibody (page 839, right column). Beiboer et al. highlighted that maintaining the VH-CDR3 sequence in a guide phage display is sufficient to screen for a human antibody with similar binding properties as the parent antibody (page 841, left column). The findings from Beiboer et al. highlighted that a skill artisan cannot predict the structural features of the antibody that will be obtained from a phage display screen when starting with a partial sequence. These findings showed that a skill artisan cannot predict the structural features of the antibody that will be obtained from a phage display screen when starting with a partial sequence, and cannot even predict the minimal structural feature of the antibody that will be obtained with a partial disclosed antibody CDR sequence that will have specific binding properties.
Regarding residue modification in the CDRs:
Applicant has not disclosed relevant, identifying characteristics of CDR region
amino acid sequences (or combinations thereof) that confer upon an antibody the ability
to bind PSCA, because the instant specification does not provide structural antibody features that correlate with a functional ability to bind PSCA.
To elaborate on why the claimed antibodies, lack adequate written description, Dondelinger et al. (Frontiers in Immunology, 9: 2278, 2018) reviews the structural basis of antigen-antibody recognition and teaches that naturally occurring conventional antibodies comprise two polypeptides, the so-called light and heavy chains. The antigen-combining site of an antibody is a three-dimensional structure that fully comprises six CDRs, three each from the light and heavy chains. The amino acid sequences of the CDRs are hypervariable, as the amino acid residues contained within the CDRs determine much of the antibody’s binding specificity. While the prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen binding domains. Lin et al. (African Journal of Biotechnology, 10(79):18294-18302, 2011) teaches that a single amino acid substitution in the VL CDR3 of an anti-avian infectious bronchitis virus (IBV) single-chain antibody (ZL.80) may abrogate binding. For example, at Figure 3, Lin et al. demonstrate that replacing either the Cys105 or Asp106 residue in the VL CDR3 of ZL.80 with an alanine residue reduces binding to near negative control levels. Lin et al. also teaches that some single amino acid substitutions in the VL CDR3 of ZL.80 may significantly improve binding. For example, replacing the Val108 residue in the VL CDR3 of ZL.80 with a tyrosine residue results in a 12.9-fold increase in affinity compared to parental ZL.80.
As discussed above, specific human antibodies can be isolated from phage display libraries. However, without performing the complex random screens to isolate the antibodies, a skilled artisan cannot predict the specific antibody structure or sequence of the claimed antibody. Because of the unpredictability of the art, the applicant has not shown they are in possession of the genus of antibodies that can function with the disclosed 1-5 amino acid residue modifications to the scFV comprising SEQ ID NOs: 32-35 respectively or a single set of 3 CDRs, that can bind to PSCA as claimed. The variation encompassed by the present claims is large and the specification does not establish that the species described are representative of the claimed subgenus. Neither does the disclosure provide sufficient evidence of the structure function relationship to provide the claimed function(s).
It is noted that, “[r]egardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to the subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.” University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1984 (CAFC 2004) (emphasis added). In this case, a skilled artisan cannot visualize the subgenus of antibodies that would bind to TCRβ V12 by the disclosure of a partial antibody sequence as the instant claim broadly claimed.
Further, absent empirical determination, one skilled in the art would be
unable to predict or envision which CDR residues within the claimed PSCA consensus sequences may be changed such that the resultant variant CDRs may be comprised of an antigen-binding site capable of binding PSCA. The general knowledge and level of skill in the art does not adequately supplement the omitted description, because specific, not general, guidance is needed. Since the disclosure fails to describe relevant, identifying structural characteristics, that correlate with the ability to bind PSCA, and because the disclosed species are not sufficient to describe the claimed genus, it is submitted that the written description requirement of 35 U.S.C. 112(a) has not been met.
The disclosure therefore does not show that applicant was in possession of the necessary common attributes or features possessed by the members of the claimed genus. Accordingly, the skilled artisan would not recognize that applicants were in possession of the invention as broadly claimed at the time the application was filed.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 12, 14, 20, 24, 32, 35, 40, 47, 62, and 66 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ma (WO 2020/077356 A1; PTO-892).
Regarding claims 1 and 47, Ma teaches an engineered cell comprising: (i) a first chimeric antigen receptor polypeptide comprising a first antigen recognition domain; a first signal peptide; a first hinge region; a first transmembrane domain; a first co-stimulatory domain; and a first signaling domain; (ii) at least one cytokine selected from the group consisting … IL-15, IL-l5/IL-l5sushi, IL-15/IL- 15 sushi anchor…and (iii) at least one chemokine (claim 1). Ma further teaches that the target surface cell antigen is PSCA (page 50, lines 18-19). Ma further teaches the present disclosure further provides a polynucleotide encoding the chimeric antigen receptor polypeptide (page 53, lines 11-12) and embodiments of CAR engineered cells that includes secreting IL-15/ IL-15 sushi and corresponding polynucleotide (page 172, lines 15-17). Ma further teaches that each unit of CAR bears a scFv against the antigen, a hinge domain (H), a transmembrane domain (TM), a co-stimulatory domain (including, but not limited to, CD28 or 4-1BB) and the intracellular signaling domain CD3 zeta chain (page 22, lines 3-6).
Regarding claims 12, 14, and 20, Ma teaches a CAR construct with a SEQ ID NO: 50 (page 64, line 7), which has 100% sequence identity to the instant claimed SEQ ID NO: 8, 18, 22, and 31 and 98.2% sequence identity to the instant claimed SEQ ID NO: 21.
Regarding claim 24, Ma teaches in one embodiment, the disclosure provides a CD123-CD33-IL-15/IL-15sushi CAR engineered cell that includes secreting IL-15/IL-15sushi (SEQ ID NO. 24) (page 85, lines 5-6), SEQ ID NO: 24 has 100% sequence identity to the instant claimed SEQ ID NO: 43.
Regarding claim 32, Ma teaches in some embodiments, CAR having an antigen recognition domain (s) is part of an expression cassette. In a preferred embodiment, the expressing gene or the cassette may include an accessory gene or a tag or a part thereof. The accessory gene may be an inducible suicide gene or a part thereof, including, but not limited to, truncated EGFR gene (EGFRt) (page 4, lines 9-15).
Regarding claim 35, Ma teaches at least one CAR unit and enhancer is expressed in a T or NK cell using bicistronic or multicistronic expression vectors and there are several strategies which can be employed to construct bicistronic or multicistronic vectors including, but not limited to, (1) multiple promoters fused to the CARs’ open reading frames;(2) insertion of splicing signals between units of CAR; fusion of CARs whose expressions are driven by a single promoter;(3) insertion of proteolytic cleavage sites between units of CAR (self-cleavage peptide); and (4) insertion of internal ribosomal entry sites (IRESs) (page 107, lines 25-31). Ma further teaches in a preferred embodiment, at least one CAR unit and an enhancer are expressed in a single open reading frame (ORF), thereby creating a single polypeptide having at least one CAR unit and an enhancer with a linker containing a high efficiency cleavage site disposed between the CAR unit and enhancer (page 108, lines 3-7). Although the specific 5’ to 3’ order is not listed with self cleaving linkers between each element the order does not matter, therefore resulting in some order of PSCA CAR-self cleaving linker - tEGFR - self cleaving linker - IL15/IL15sushi.
Regarding claims 40 and 47, Ma teaches sorted NK-92 cells or T cells transduced with various CAR- IL15 lentiviral vectors (Figure 65A).
Regarding claim 66, Ma teaches the present disclosure provides a method of reducing the number of target cells including the steps of (i.) contacting said target cells with an effective amount of an engineered cell having at least one chimeric antigen receptor polypeptide and (ii.) optionally, assaying for the reduction in the number of said cells…wherein the target is PSCA (page 3, lines 24-30). Ma teaches wherein the engineered cell is a T-cell, NKT cell, Natural Killer cell, or NK92 cell (claim 11). Ma further teaches that the cells may be autologous, syngeneic, allogeneic, or xenogeneic to the recipient of the engineered cells (page 60, lines 21-22).
Regarding claim 62, Ma teaches a method of treating a cell proliferation disease, said method comprising: administering to a patient in need thereof an engineered cell according to any one of claims 1-14 (claim 15), wherein said cell proliferation disease comprises soft tissue tumor or solid tumor, carcinoma, or sarcoma (claim 16).
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 2-6, 11 23, and 59 are rejected under 35 U.S.C. 103 as being unpatentable over Ma (WO 2020/077356 A1; PTO-892) as applied to claims 1, 12, 14, 20, 24, 32, 35, 40, 47, 62, and 66 above, and further in view of Chan (US 2017/0051044 A1; PTO-892).
The teachings of Ma regarding claims 1, 12, 14, 20, 24, 32, 35, 40, 47, 62, and 66 are detailed above.
Ma does not teach wherein the PSCA-scFv comprises SEQ ID NO: 32 and 33.
Regarding claims 2-6, Chan teaches antigen binding constructs that bind the PSCA antigen can be antibodies, minibodies and/or fragments thereof such as scFv, including SEQ ID NO: 127 (para 0283), SEQ ID NO: 127 has 100% sequence identity to the instant claimed SEQ ID NO: 32 and 33.
Regarding claims 11 and 23, Chan teaches scFv linker sequence comprising SEQ ID NO: 64, therefore teaching 100% of the instant claimed SEQ ID NO: 40.
Regarding claim 59, Chan further teaches provided herein are methods for treating a subject having cancer, or inhibiting the growth of a prostate cancer cell expressing a Prostate Stem Cell Antigen (PSCA) protein comprising contacting the cancer cell (e.g., prostate, bladder, pancreatic cancer cell, with a construct as provided herein, in an amount effective to inhibit the growth of the cancer cell (para 0370).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to use the scFv sequences as taught by Chan in the PSCA-CAR-tEGFR-IL15/IL15sushi construct as taught by Ma. The ordinary artisan would have been motivated to do so because Chan teaches PSCA targeting scFvs that can be used to inhibit the growth of PSCA expressing cancer cells. The ordinary artisan has a reasonable expectation of success in substituting a known PSCA scFv sequence into the PSCA-CAR-tEGFR-IL15/IL15sushi.
Claims 7-10 and 65 are rejected under 35 U.S.C. 103 as being unpatentable over Ma (WO 2020/077356 A1; PTO-892) as applied to claims 1, 12, 14, 20, 24, 32, 35, 40, 47, 62, and 66 above, and further in view of Bachmann (US 9,200,078 B2; PTO-892).
The teachings of Ma regarding claims 1, 12, 14, 20, 24, 32, 35, 40, 47, 62, and 66 are detailed above.
Ma does not teach wherein the PSCA-scFv comprises SEQ ID NO: 34 and 35 or specifically treating a cancer expressing PSCA.
Regarding claims 7-10, Bachmann teaches a prostate-specific stem cell antigen binding antibody (claim 1), and a nucleic acid whose nucleotide sequence encodes for an antibody according to claim 1 (claim 9), wherein the humanized variable region of the light chain SEQ ID No. 24, variable region of the heavy chain SEQ ID No. 26 (column 12, lines 26-27). SEQ ID NO: 24 and 26 have 100% sequence identity to the instant claimed SEQ ID NO: 34 and 35 respectively. Bachmann further teaches that the antibodies are suitable for use in the areas of medicine, pharmacy and biomedical research (abstract).
Regarding claim 65, Bachmann teaches a therapeutic use of the PSCA antibodies according to the invention is the treatment of tumor diseases, preferably prostate cancer (column 7, lines 14-16). Bachmann further teaches the prostate-specific stem cell antigen (PSCA) is a surface molecule which is present specifically on prostate cells and is expressed at a higher rate in prostate carcinoma cells in comparison to healthy tissue (tumor-associated antigen).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to use the VH and VL sequences as taught by Bachmann in the PSCA-CAR-tEGFR-IL15/IL15sushi construct as taught by Ma. The ordinary artisan would have been motivated to do so because Bachmann teaches a humanized PSCA binding antibody that can be used to treat tumors and more specifically prostate cancer. The ordinary artisan has a reasonable expectation of success in substituting a known PSCA binding antibody VH and VL sequence into the PSCA-CAR-tEGFR-IL15/IL15sushi.
Claim 28 is rejected under 35 U.S.C. 103 as being unpatentable over Ma (WO 2020/077356 A1; PTO-892) as applied to claims 1, 12, 14, 20, 24, 32, 35, 40, 47, 62, and 66 above, and further in view of Felber (US 9,303,080 B2; PTO-892).
The teachings of Ma regarding claims 1, 12, 14, 20, 24, 32, 35, 40, 47, 62, and 66 are detailed above.
Ma does not teach wherein the IL-15R alpha comprises SEQ ID NO: 72.
Felber teaches a codon optimized nucleic acids for improved expression of IL-15 and IL-15R alpha genes in mammalian cells (title and abstract). Fig 37 discloses an improved soluble IL15Ra with an encoded amino acid sequence of SEQ ID NO: 50, which has 100% sequence identity to the instant claimed SEQ ID NO: 72. Felber further teaches that the present methods are useful for the increased bioavailability and biological effects of IL-15 after DNA, RNA or protein administration in a subject (abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to use the IL-15R alpha gene sequences as taught by Felber in the PSCA-CAR-tEGFR-IL15/IL15sushi construct as taught by Ma. The ordinary artisan would have been motivated to do so because Felber teaches a codon optimized nucleic acids for improved expression of IL-15 and IL-15R alpha genes in mammalian cells to increase the bioavailability and biological effect. The ordinary artisan has a reasonable expectation of success in substituting a known IL-15 sequence into the PSCA-CAR-tEGFR-IL15/IL15sushi.
The rationale to apply a technique taught by the prior art as improving the therapeutic and production characteristics of a similar construct is to predictably obtain an improvement to the second construct and is consistent with the exemplary rationales provided by the Supreme Court in KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1395-97 (2007) and discussed in M.P.E.P. § 2143. For these reasons, the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention.
Claim 38 is rejected under 35 U.S.C. 103 as being unpatentable over Ma (WO 2020/077356 A1; PTO-892) as applied to claims 1, 12, 14, 20, 24, 32, 35, 40, 47, 62, and 66 above, and further in view of Yang (US 7,939,059 B2; PTO-892).
The teachings of Ma regarding claims 1, 12, 14, 20, 24, 32, 35, 40, 47, 62, and 66 are detailed above.
Ma does not teach wherein the nucleic acid molecule further comprises SEQ ID NO: 46 or 47.
Yang teaches a method of producing a population of antigen-specific T cells in a mammal comprising: contacting a hematopoietic stem cell ex vivo with a polynucleotide delivery system comprising an antigen-specific polynucleotide such that the antigen-specific polynucleotide is expressed in the hematopoietic stem cell and directs the differentiation of the hematopoietic stem cell into the antigen-specific T cell; and transferring the hematopoietic stem cell into the mammal, wherein the polynucleotide delivery system comprises a single promoter operably linked to the antigen-specific polynucleotide (claim 1), wherein an IRES element or 2A element is disposed between a first and second portion of the antigen-specific polynucleotide (claim 3). Yang further teaches that 2A sequences are small peptides introduced as a linker between two proteins, allowing autonomous intraribosomal self-processing of polyproteins for coexpression of multiple proteins from a single vector and an exemplary example of a 2A sequence is Thosea asigna virus (T2A) (SEQ ID NO: 8). Yang further teaches that the 2A peptide is separated (“cleaved”) at its own C-terminus co-translationally between the glycine and proline amino acids and that separation is mediated by a novel translational effect (a putative ribosomal “skip”) (column 16, lines 7-26), SEQ ID NO: 8 has 100% sequence identity to instant claimed SEQ ID NO: 46.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to add a 2A sequence as taught by Yang to the PSCA-CAR-tEGFR-IL15/IL15sushi construct as taught by Ma. The ordinary artisan would have been motivated to do so because Yang teaches 2A sequences are small peptides introduced as a linker between two proteins, allowing autonomous intraribosomal self-processing of polyproteins for coexpression of multiple proteins from a single vector. The ordinary artisan has a reasonable expectation of success in adding a known 2a sequence into the PSCA-CAR-tEGFR-IL15/IL15sushi to allow coexpression of multiple proteins from a single vector.
The rationale to apply a technique taught by the prior art as improving the therapeutic and production characteristics of a similar construct is to predictably obtain an improvement to the second construct and is consistent with the exemplary rationales provided by the Supreme Court in KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1395-97 (2007) and discussed in M.P.E.P. § 2143. For these reasons, the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention.
Claim 82 is rejected under 35 U.S.C. 103 as being unpatentable over Ma (WO 2020/077356 A1; PTO-892) as applied to claims 1, 12, 14, 20, 24, 32, 35, 40, 47, 62, and 66 above, and further in view of Ueda (Cancer Sci. 2020; 111: 1478–1490; PTO-892).
The teachings of Ma regarding claims 1, 12, 14, 20, 24, 32, 35, 40, 47, 62, and 66 are detailed above.
Ma does not teach wherein the NK cells transduced by a vector are stable after one, two or three freeze-thaw cycles.
Regarding claims 82, Ueda teaches generation of NK cells from pluripotent stem cells that express a CAR-tEGFR construct with verified cytotoxicity and cytokine production (abstract). Ueda further teaches generation of a master cell bank suitable for non-clinical testing and clinical trials (section 3.3). Ueda further teaches the frozen iCAR-NK/ILC cells maintained sufficient viability during shipment to a non–clinical test site, approximately 500 km from the production facility, and also maintained cell numbers and viability for 3 hours after thawing, when kept on ice, until injection into the test animals (section 3.3 and Table 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to generate transduced NK cells that are stable through freeze/ thaw cycle as taught by Ueda with the PSCA-CAR-tEGFR-IL15/IL15sushi construct as taught by Ma. The ordinary artisan would have been motivated to do so because Ueda teaches generation of a master cell bank after transduction to use for non-clinical and clinical testing, as well as for shipment to test sites. The ordinary artisan has a reasonable expectation of success to generate freeze/ thaw stable NK cells transduced with the PSCA-CAR-tEGFR-IL15/IL15sushi as a benefit of repeated testing the same lot and ability to ship to different test sites.
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 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); 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 nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1-6, 11-12, 14, 23, and 47 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 8, and 11 of U.S. Patent No. 11,466,097 in view of DeRenzo (Front Immunol. 2019 Feb 15;10:218; PTO-892).
Regarding claim 1-6, the patented claims teach a nucleic acid molecule encoding a chimeric antigen receptor comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 26, 28, 30, 32, 34 and 36 (claim 1, 4-5, and 11). SEQ ID NO: 26 has 100% sequence identity to the instant claimed SEQ ID NO: 32 and 33.
Regarding claims 11 and 23, SEQ ID NO: 26 has 97.4% sequence identity to the instant claimed SEQ ID NO: 1, with 5 amino acids changed in the linker and could thereby be considered an equivalent.
Regarding claim 12 and 14, SEQ ID NO: 26 has 100% sequence identity to the instant claimed SEQ ID NO: 12, 16, 21, and 24.
Regarding claim 47, the patented claims teach a population of human T cells comprising a nucleic acid encoding a chimeric antigen receptor comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 26, 28, 30, 32, 34 and 36 (claims 2-3 and 8).
The patented claims do not teach a second nucleotide molecule encoding an IL-15 domain.
Regarding claim 1, DeRenzo teaches constitutively expressed IL-15 can be engineered by tethering IL-15 to the cell membrane or secreted by modified T cells and that CAR T cells modified to secrete IL-15 demonstrated superior proliferative capacity and antitumor activity in vitro and in vivo compared to the CAR alone (page 4, column 1, para 4; Fig 2D). DeRenzo further teaches that after 4 weeks IL-15 expressing CAR T cells had greater activity indicating that IL15 improved T cell persistence over a prolonged period of time (page 4, column 1, para 4; Fig 2D).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to add an IL-15 nucleotide as taught by DeRenzo to the PSCA-CAR construct in T cells as taught by the patented claims. The ordinary artisan would have been motivated to do so because DeRenzo teaches that CAR T cells modified to secrete IL-15 demonstrated superior proliferative capacity and antitumor activity in vitro and in vivo compared to the CAR alone, as well as improved persistence. The ordinary artisan has a reasonable expectation of success in adding a known IL-15 nucleotide to the PSCA-CAR T cells to improve performance and longevity of immunotherapy.
The rationale to apply a technique taught by the prior art as improving the therapeutic and production characteristics of a similar construct is to predictably obtain an improvement to the second construct and is consistent with the exemplary rationales provided by the Supreme Court in KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1395-97 (2007) and discussed in M.P.E.P. § 2143. For these reasons, the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention.
Claims 1-6, 12, 14, 47 and 62 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 29-36 and 38-42 of copending Application No. 17/820,440 (this application has been allowed but has not yet been published) in view of DeRenzo (Front Immunol. 2019 Feb 15;10:218; PTO-892).
This is a provisional nonstatutory double patenting rejection.
Regarding claims 1-6, 12, and 14, the copending claims teach a nucleic acid molecule encoding a chimeric antigen receptor (CAR) selected from the group consisting of: a CAR comprising a PSCA scFV (claim 29), wherein the CAR comprises: PSCA scFV comprising the amino acid sequence of SEQ ID NO: 38, a spacer comprising the amino acid sequence of SEQ ID NO: 9, a CD4 transmembrane domain comprising the amino acid sequence of SEQ ID NO: 16, a 41-BB co-stimulatory domain comprising the amino acid sequence of SEQ ID NO: 24, and CD3ζ domain comprising the amino acid sequence of SEQ ID NO: 21 (claim 30-32 and 38-41). SEQ ID NO: 38 has 100% sequence identity to the instant claimed SEQ ID NO: 32 and 33. SEQ ID NO: 16, 21, 24, has 100% sequence identity to the instant claimed same SEQ ID NOs.
Regarding claim 47, the copending claims teach a population of human T cells comprising a nucleic acid encoding a CAR selected from the group consisting of: a CAR comprising a PSCA scFV comprising the amino acid sequence of SEQ ID NO: 38, a spacer comprising the amino acid sequence of SEQ ID NO: 9, a CD4 transmembrane domain comprising the amino acid sequence of SEQ ID NO: 16, a 41-BB co-stimulatory domain comprising the amino acid sequence of SEQ ID NO: 24, and CD3ζ domain comprising the amino acid sequence of SEQ ID NO: 21 (claims 33-36).
Regarding claim 62, the copending claims teach a method for treating a human patient having a cancer expressing prostate specific antigen, the method comprising administering to the patient the population of human T cells of claim 33 (claim 42).
The copending claims do not teach a second nucleotide molecule encoding an IL-15 domain.
Regarding claim 1, DeRenzo teaches constitutively expressed IL-15 can be engineered by tethering IL-15 to the cell membrane or secreted by modified T cells and that CAR T cells modified to secrete IL-15 demonstrated superior proliferative capacity and antitumor activity in vitro and in vivo compared to the CAR alone (page 4, column 1, para 4; Fig 2D). DeRenzo further teaches that after 4 weeks IL-15 expressing CAR T cells had greater activity indicating that IL15 improved T cell persistence over a prolonged period of time (page 4, column 1, para 4; Fig 2D).
It would have been obvious to one of ordinary skill in the art to add an IL-15 nucleotide as taught by DeRenzo to the PSCA-CAR construct in T cells as taught by the patented claims. The ordinary artisan would have been motivated to do so because DeRenzo teaches that CAR T cells modified to secrete IL-15 demonstrated superior proliferative capacity and antitumor activity in vitro and in vivo compared to the CAR alone, as well as improved persistence. The ordinary artisan has a reasonable expectation of success in adding a known IL-15 nucleotide to the PSCA-CAR T cells to improve performance and longevity of immunotherapy.
The rationale to apply a technique taught by the prior art as improving the therapeutic and production characteristics of a similar construct is to predictably obtain an improvement to the second construct and is consistent with the exemplary rationales provided by the Supreme Court in KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1395-97 (2007) and discussed in M.P.E.P. § 2143. For these reasons, the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention.
Claims 1-6, 12, 14, 24, 28, 47, 62, and 65-66 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 5-6, 13, 16-18, 20 and 23 of copending Application No. 18/981,030 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding claims 1-4 and 47, the copending claims teach a population of cells comprising NKT cells (NKT cells) harboring: (a) a nucleic acid molecule encoding both: a chimeric antigen receptor (CAR), the CAR comprising: a single chain variable domain (scFv) targeting prostate stem cell antigen (PSCA), a spacer, a transmembrane domain, a co-stimulatory domain, and a CD3ζ; signaling domain; and polypeptide comprising a human IL-15 domain that binds to IL-15 receptor; or (b) a first nucleic acid molecule encoding a chimeric antigen receptor (CAR), the CAR comprising: a single chain variable domain (scFv) targeting prostate stem cell antigen (PSCA), a spacer, a transmembrane domain, a co-stimulatory domain, and a CD3ζ; signaling domain and second nucleic acid molecule encoding a polypeptide comprising a human IL-15 domain that binds to rL-15 receptor wherein the scFv comprises a variable heavy chain (BC) and a variable light chain (LC), wherein the BC comprises complementarity-determining regions: CDRH1 comprising the amino acid sequence of SEQ ID NO: 50, CDRH2 comprising the amino acid sequence of SEQ ID NO: 51 and CDRH3 comprising the amino acid sequence of GGF, and wherein the LC comprises complementarity-determining regions: CDRL1 comprising the amino acid sequence of SEQ ID NO: 53. CDRL2 comprising the amino acid sequence of SEQ ID NO: 54, and CDRL3 comprising the amino acid sequence of SEQ ID NO: 55 (claim 1). Instant claimed SEQ ID NO: 33 has 100% sequence identity to SEQ ID NO: 50, 51, and GGF. Instant claimed SEQ ID NO: 32 has 100% sequence identity to SEQ ID NO: 53-55.
Regarding claims 5-6, the copending claims teach the population of cells of claim 1 or claim 2, wherein the scFv comprises or consists of the amino acid sequence of SEQ ID NOs: 1, 40, or a variant thereof (claim 5). SEQ ID NO: 1 has 100% sequence identity to the instant claimed SEQ ID NO: 32 and 33.
Regarding claims 12 and 14, the copending claims teach the population of cells of claim 1, wherein: (a) the spacer comprises or consists of the amino acid sequence of any of SEQ ID NOs: 3-12 and 28; (b) the transmembrane domain comprises or consists of the amino acid sequence of any of SEQ ID NOs: 13-20 and 34; (c) costimulatory domain comprises or consists of the amino acid sequence of any of SEQ ID NOs: 22-26; (d) the spacer comprises or consists of the amino acid sequence of any of SEQ ID NOs: 3-12 and 28; the transmembrane domain comprises or consists of the amino acid sequence of any of SEQ ID NOs: 13-20 and 34; costimulatory domain comprises or consists of the amino acid sequence of any of SEQ ID NOs: 22-26; and the CD3ζ signaling domain comprises or consists of the amino acid sequence of SEQ ID NO: 21 or a variant thereof selected from SEQ ID NOs: 56-62 (claim 6). SEQ ID NOs: 12-13 and 21-22, have 100% sequence identity to the same SEQ ID NO in the instant claims.
Regarding claim 24, the copending claims teach the population of cell of claim 1, claim 11 or claim 12, wherein the human IL-15 domain comprises or consists of the amino acid sequence of any of SEQ ID NOs: 63-65 (claim 13). SEQ ID NO: 63 has 100% sequence identity to the instant claimed SEQ ID NO: 43.
Regarding claim 28, the copending claims teach wherein the cells comprise a nucleic acid molecule encoding a PSCA CAR followed by a skip sequence, a signal sequence and an IL-15 domain wherein the PSCA CAR includes a signal sequence (claim 16).
Regarding claims 62, the copending claims teach a method for treating a cancer or a solid tumor that expresses PSCA in a human subject in need thereof, comprising administering the subject a therapeutically effective composition comprising the population of cells of claim 17 (claim 18).
Regarding claim 65, the copending claims teach wherein the solid tumor or cancer is any one or more of: a gall bladder cancer, a gall bladder adenocarcinoma, a pancreatic cancer, a PSCAexpressing NSCLC, a prostate cancer, a urinary bladder cancer, a cervical cancer, an esophageal cancer, or a gastric cancer (claim 23), wherein the cells comprise natural killer cells (NK cells), natural killer T cells (NKT cells) or both (claim 17).
Regarding claim 66, the copending claims teach a method of reducing PSCA-positive cells in a human subject comprising administering the subject a composition comprising the population of cells of claim 17 (claim 20), wherein the cells comprise natural killer cells (NK cells), natural killer T cells (NKT cells) or both (claim 17).
This is a provisional nonstatutory double patenting rejection.
Conclusion
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/AMBER K FAUST/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643