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
Election/Restriction
Applicant’s election, without traverse, of Group I, claims 1-4, 6, 7, 9, 11, 12, 16, 19, and 22-24, drawn to a polynucleotide construct and an engineered cell expressing the construct, in the reply filed on 05/28/2025 is acknowledged.
Claims 28-31, 33 and 34 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Amendment
In the reply filed on 05/28/2025, Applicant has amended claims 1, 2, 4, 6, 9, 11, 12, 22, 28-30 and 33, added new claim 45 and canceled claims 3 and 7.
Claim Status
Claims 1-2, 4, 6, 9, 11-12, 16, 19, 22-24, 28-31, 33-34 and 45 are pending.
Claims 28-31 and 33-34 are withdrawn.
Claims 1-2, 4, 6, 9, 11-12, 16, 19, 22-24 and 45 are considered on the merits.
Priority
This application is a 371 of PCT/US2020/056723 (filed on 10/21/2020), which claims benefit from Application No. 62/923,644 (filed on 10/21/2019). The priority claim of the instant application has been granted and the earliest benefit date is 10/21/2019 from the Application No. 62/923,644.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 04/20/2022 and 05/13/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner. The corresponding signed and initialed PTO forms 1449 have been mailed with this action.
Claim Objections
Claims 1, 16 and 23 are objected to because of the following informalities:
Claim 1 recites a second sequence encoding “at least anti-GD2 scFv”. It is recommended to change to “at least an anti-GD2 scFv”.
Claim 16 recites “one or more signaling domains” in line 2. Since the base claim 12 has already recited “one or more signaling domains”, it is recommended to change the phrase in claim 16 to “the one or more signaling domains”.
Furthermore, claim 16 recites “a tumor necrosis factor receptor superfamily member 9 (TNFRSF9 or 4-1BB)” and “CD137”. Since TNFRSF9, 4-1BB and CD137 are merely different names for the same molecule, it is recommended to remove CD137 and recite as “(TNFRSF9, 4-1BB or CD137)”.
Claim 23 recites “a polynucleotide construct according to claim 1”. Since claim 1 recites “a polynucleotide construct”. It is recommended to change the phrase to “the polynucleotide construct according to claim 1”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 22 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 22 recites the limitation that the first sequence encodes a first amino acid that has at least a 90% sequence identity to SEQ ID NO: 7 and the second sequence encodes a second amino acid that has at least 90% sequence identity to SEQ ID NO: 6. It is noted that SEQ ID NO: 7 is directed to an anti-GD2 CAR and SEQ ID NO: 6 is directed to an NKG2D CAR. However, claim 1 recites the first sequence encoding an NK activating receptor (such as NKG2D in claims 6 and 9) and the second sequence encoding an anti-GD2 scFv. Thus, claim 22 recites a different first sequence and a different second sequence from that of claim 1. For the sake of compact prosecution, claim 22 is examined as “the first sequence encodes a first amino acid that has at least a 90% sequence identity to SEQ ID NO: 6 and the second sequence encodes a second amino acid that has at least 90% sequence identity to SEQ ID NO: 7”.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112(a)
(Written Description)
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 22 and 24 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.
Under the new Written Description Guidelines for antigen binding proteins molecules, the Examiner is directed to determine whether one skilled in the art would recognize that the applicant was in possession of the claimed invention as a whole at the time of filing. The following considerations are critical to this determination: on 22 February 2018, the USPTO provided a Memorandum clarifying the Written Description Guidelines for claims drawn to antibodies, which can be found at www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf. That Memorandum indicates that, in compliance with recent legal decisions, the disclosure of a fully characterized antigen no longer is sufficient written description of an antibody to that antigen. Accordingly, the instant claims have been re-evaluated in view of that guidance.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
SCOPE OF THE INVENTION
Claim 22 encompasses a genus of polynucleotide constructs in which the first sequence encodes a first amino acid that has at least a 90% sequence identity to SEQ ID NO: 6 and the second sequence encodes a second amino acid that has at least 90% sequence identity to SEQ ID NO: 7, and claim 24 encompasses a genus of engineered cells expressing an amino acid sequence that has at least a 90% sequence identity to SEQ ID NO: 8. It is noted that in the base claim 1 the first and the second sequences encode a natural killer activating receptor or an anti-GD2 scFV.
In the context of the sizes of SEQ ID NO: 6 (451 amino acids), SEQ ID NO: 7 (469 amino acids) and SEQ ID NO: 8 (1212 amino acids), the claimed scope encompasses a genus comprising an astronomical number of amino acid sequences in which 45 amino acids, 46 amino acids or 121 amino acids can be deleted or mutated to any amino acid, in any combination, at any position. However, the specification only discloses a single amino acid sequence of SEQ ID NO: 6, a single amino acid sequence of SEQ ID NO: 7 and a single amino acid sequence of SEQ ID NO: 8.
ACTUAL REDUCTION TO PRACTICE
As stated supra, Claims 22 and 24 have a much broader scope compared to that is disclosed in the specification. Specifically, Applicant has only disclosed in the specification a single species of each claimed sequence. Thus, Applicant fails to show actual reduction to practice the broad scope as being claimed.
DISCLOSURE OF STRUCTURE
The Applicant has provided a single species of the claimed sequences that may function as a natural killer activating receptor or may bind to a GD2 antigen. However, neither the specification nor the art indicate a relationship between the structure of the claimed genus of polynucleotide constructs or engineered cells with the claimed amino acid sequences and the ability to function as a natural killer activating receptor or to bind to a GD2 antigen. Thus, the specification does not support the broad scope of the claims. Furthermore, applicants have not provided sufficient guidance to enable one of ordinary skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims. Without sufficient guidance, making a polynucleotide construct or engineered cell by mutating up to 45, 46 or 121 amino acids to any amino acids in any combination at any position to retain the function of an NK activating receptor or an anti-GD2 scFv antibody is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731,8 USPQ2nd 1400 (Fed. Cir, 1988).
SUFFICIENT RELEVANT IDENTIFYING CHARACTERISTICS
Making a mutated polynucleotide construct or an engineered cell is known. Accordingly, if the skilled artisan sought to make the claimed genus of mutated constructs or cells, they would first need to know which amino acids to start with, what amino acids to mutate to, what combination of the amino acids to mutate, while still be able to predicably produce functional NK activating receptors and anti-GD2 antibodies. Hence, based on the new written description guidelines, the Examiner should conclude that the applicant was not in possession of the claimed genus of constructs or cells.
The breath of the claims encompasses a very broad genus of amino acid sequences encoded and expressed by the claimed constructs and cells. However, the present specification provides no guidance nor description to any rational in choosing how to choose the candidate amino acids to mutate or what amino acids to mutate to, therefore the skilled artisan would not know what rational approach to take to make modifications with any predictable outcome on producing functional NK activating receptors or anti-GD2 antibodies. Therefore, it is incumbent on the applicant to provide this nexus between structure and function, in order to be given credit for possession of a larger genus of sequences related to those individual species. Otherwise, the Written Description guidelines suggest that the applicant is entitled to only the species specifically recited as having this activity. Moreover, even when several species are disclosed, these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species.
An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.
STATE OF THE ART & QUANTITY OF EXPERIMENTATION
The method of making the claimed invention is not well established. Although making a polynucleotide construct encoding a mutated amino acid sequence and transfecting this to a cell is known, one of skill in the art would neither expect nor predict the function of NK activating receptors or anti-GD2 antibodies as claimed in the genus of constructs or cells as broadly as is claimed.
Regarding maintaining antibody specificity while mutating amino acids of the antibody, Torres et al., (Trends Immunol. 2008;29(2):91-7) summarizes the state of the art in the field of antibody specificity determination. Torres teaches not only variable (V)-region contributes to antibody specificity, which is well known, numerous reports have demonstrated that constant heavy (CH) domains can affect binding affinity and specificity and V-region structure (e.g., abstract). Thus, Torres evidences that mutating amino acids in any position to any amino acids, while maintaining the antibody specificity, is highly unpredictable.
Applicant has claimed a genus of polynucleotide constructs or cells that encode or express a broad scope of amino acid sequences while maintaining the function of the NK activating receptor or the anti-GD2 antibody specificity, yet the specification has only disclosed a single species of each of the amino acid sequence. Independent of how these specific sequences were arrived upon by Applicant, any mutated amino acid sequence cannot be predicably produced while maintaining the function of an NK activating receptor or an anti-GD2 antibody. Because Applicant has no manner a priori to predict what combination/modification can be done to produce those mutated amino acid sequences, the genus of polynucleotide constructs or cells claimed by Applicant cannot be predictably made or used by the ordinary artisan.
CONCLUSION
Therefore, the examiner concludes that there is insufficient written description of the instantly claimed genus. Specifically, there is limited description of the structure-function relationship between the claimed genus of amino acid sequences and their ability to maintain function of the NK activating receptor or anti-GD2 antibody, and the Examiner further concludes a skilled artisan would find the specification inadequately describes the sequences encompassed by the claimed genus.
Therefore, the specification fails to provide sufficient written description to inform a skilled artisan that inventors were in possession of the entire scope of the claimed invention.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 6, 9, 11, 12, 16, 19, 23 and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Campana et al., (US Patent No. 9,511,092) in view of Pule et al., (US 2017/0066838) and Fry et al., (WO 2018/213337).
Claim 1 is directed to a polynucleotide construct comprising a first sequence encoding an NK activating receptor and a second sequence encoding an anti-GD2 scFv operably linked to the NK activating receptor.
Campana teaches a chimeric receptor comprising NKG2D, DAP10 and CD3 zeta, a polynucleotide encoding the chimeric receptor and the expressing of the chimeric receptor in activated NK cells (e.g., col. 2, para “Brief Summary”). Campana teaches NKG2D is a key receptor for NK cell activation (col. 1, lines 59-60), thus teaches NKG2D is an NK activating receptor. Thus, Campana teaches a polynucleotide construct comprising a first sequence encoding an NK activating receptor. Campana teaches NKG2D chimeric receptor engineered NK cells can be used for treating a cancer such as sarcoma (e.g., col. 6, para 2-3).
However, Campana is silent on a second sequence encoding an anti-GD2 scFv.
Pule teaches an anti-GD2 CAR that comprises an anti-GD2 scFv as antigen-binding domain (abstract, see e.g., Fig 1 and [0043-0044]). Pule teaches a nucleic acid sequence which encodes the CAR ([0060-0064]), a cytolytic immune cell, such as an NK cell comprising the CAR ([0065]) and a method of treating cancer, such as sarcoma, by administering the cell comprising the CAR (e.g., [0070] and [0141-0143]).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the NK cells engineered with a polynucleotide sequence encoding an NKG2D chimeric receptor for treating a cancer such as sarcoma disclosed by Campana, by combining a second sequence encoding an anti-GD2 CAR comprising an anti-GD2 scFv as taught by Pule with a reasonable expectation of success. Since Campana teaches NKG2D chimeric receptor engineered NK cells can be used for treating a cancer such as sarcoma (e.g., col. 6, para 2-3), and since Pule teaches NK cells comprising an anti-GD2 CAR can be used for treating a cancer such as sarcoma ([0065] and [0141-0143]), one of ordinary skill in the art would have had a reason to combine a sequence encoding an anti-GD2 CAR of Pule in the NK cells comprising an NKG2D chimeric receptor of Campana in order to treat cancer such as sarcoma.
Furthermore, MPEP 2144.06 states "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted).
However, Campana and Pule do not specifically teach the two sequences encoding the NKG2D chimeric receptor and the anti-GD2 CAR are operably linked within a single polynucleotide construct.
Fry teaches a bicistronic CAR polynucleotide construct (abstract). Fry teaches the construct comprises a first CAR and a second CAR; wherein the first and second CARs are linked through a cleavable domain (e.g., [0005-0008] and see Fig 1). To compare different scenarios in combinatory therapy with two CARs (using anti-CD19 CAR and anti-CD22 CAR as an example) in treating cancer, Fry investigates (1) sequential infusion of anti-CD19-CAR T cells followed by anti-CD22 CART-cells or vice versa, but the sequential infusion does not prevent acute lymphoblastic leukemia (ALL) progression (see [0238]); (2) co-transducing both anti-CD19 and anti-CD22 CAR into the same T cell, however, co-transduction efficiency is consistently low, yielding only a quarter of the total T cell product expressing both CARs (see [0239]); (3) bivalent CARs with tandem sequencing of scFv in which two different scFv domains are tandemly coupled into a single CAR construct, but neither tandem CAR construct fully eradicates CD19posCD22pos ALL in vivo ([0240-0241]); (4) bivalent CARs with looping structure of two scFv domains ([0242-0244]), but even the optimal construct LoopCAR6 does not completely eradicate CD19neg and CD22neg leukemia ([0267]); (5) bicistronic CARs in which CD19 CAR and CD22 CAR become two separate fragments and are expressed as two CARs on the cell surface in an equal molar ([0268]), bicistronic CARs have very potent activity on clearing the leukemia and is superior to the bivalent CARs in reducing the CD19neg and CD22neg leukemia ([0273-0275]). Thus, Fry indicates that a bicistronic construct, i.e., a single polynucleotide construct comprising two CARs linked through a cleavable domain, is superior over other combinatory systems.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the combinatory CAR-NK therapy comprising an NKG2D CAR and an anti-GD2 CAR for treating a cancer such as sarcoma suggested by Campana in view of Pule, by choosing a bicistronic construct comprising a single polynucleotide construct comprising two CARs operably linked through a cleavable domain as taught by Fry with a reasonable expectation of success. Since Campana in view of Pule suggests a combinatory CAR-NK therapy for treating cancer, and since Fry investigates and teaches a bicistronic construct achieves an equal-molar expression of two CARs and has the superior therapeutic results (see [0268 and 0273-0275]), one of ordinary skill in the art would have had a reason to choose the bicistronic construct of Fry to express the two CARs of Campana in view of Pule in order to obtain an equal-molar expression of the two CARs and to obtain the superior therapeutic results.
With respect to claim 6 directed to the NK activating receptor comprising an extracellular ligand-binding domain comprising an NKG2D, as stated supra, Campana teaches the polynucleotide encoding “an extracellular ligand-binding domain comprising a Natural Killer Group 2 member D receptor (NKG2D)” (see e.g., col. 3, para 4).
With respect to claim 9 directed to the NK activating receptor comprising an extracellular ligand-binding domain comprising an NKG2D and the first sequence further encoding upregulated expression of the NKG2D as compared to expression of NKG2D in a wild-type NK cell, as stated supra, Campana teaches the polynucleotide encoding an extracellular ligand-binding domain comprising an NKG2D (see e.g., col. 3, para 4), and teaches the NKG2D chimeric receptor construct transduction results in an increase of NKG2D expression in NK cells compared to NKG2D expression in NK cells transduced with a Mock vector (equivalent to a wild-type NK cell) (see col. 53, result para 6.2.1 from line 37 and Fig 1B). Thus, Campana teaches the first sequence further encodes upregulated expression of the NKG2D compared to that in a wild-type NK cell.
With respect to claim 11 directed to the first sequence being expressed in a first CAR and the second sequence being expressed in a second CAR, as stated supra, Campana teaches a first sequence is expressed in an NKG2D chimeric receptor (equivalent to a first CAR, see e.g., col. 2, para “Brief Summary”) and Pule teaches the second sequence anti-GD2 scFv is expressed in an anti-GD2 CAR (equivalent to a second CAR, see e.g., abstract).
With respect to claim 12 directed to one of the first and second sequences encoding a signaling domain for promoting cytotoxic or cytolytic activity upon activation, and claim 16 directed to the signaling domain being DAP10 or CD3 zeta, Campana teaches the first sequence encodes a DAP10 and a CD3 zeta signaling domain (e.g., col. 2, para “Brief Summary”) and teaches “signal transduction occurs upon ligation via the phosphorylation of DAP10, which recruits downstream signaling effector molecules and, ultimately, cytotoxicity (col. 2, para 3). Thus, Campana teaches the first sequence encodes a signaling domain, such as a DAP10 and a CD3 zeta, for promoting cytotoxicity upon activation.
With respect to claim 19 directed to the first sequence further encoding a self-cleaving peptide, as stated supra, Campana, in view of Pule and Fry, suggests a bicistronic polynucleotide construct comprising a first sequence operably linked to a second sequence through a cleavable domain (equivalent to a self-cleaving peptide, see an exemplary P2A used in constructs #V5-V8 in Fry, Fig 1), thus suggests the first sequence further encodes a self-cleaving peptide.
With respect to claim 23 directed to an engineered cell expressing the polynucleotide construct of claim 1, as stated supra, Campana teaches an engineered NK cell that expresses the polynucleotide construct suggested by Campana in view of Pule and Fry (see Campana, col. 2, para “Brief Summary”).
With respect to claim 45 directed to the self-cleaving peptide being P2A, as stated supra, Fry teaches a cleavable domain (equivalent to a self-cleaving peptide) comprising a P2A (see [0071] and Constructs #V5-V8 in Fig 1).
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Claims 2 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over Campana et al., (US Patent No. 9,511,092) in view of Pule et al., (US 2017/0066838) and Fry et al., (WO 2018/213337), as applied to claim 1 above, and further in view of Hay et al., (US 2016/0129108) and Wang et al., (J Mol Med. 2018 August 1; 96: 903-913).
Claim 2 is directed to the polynucleotide construct further comprising a third sequence encoding a binding domain specific for an adenosine-producing cell surface protein and further comprising a cleavable linker. Claim 4 is directed to the binding domain comprising an antibody fragment specific for CD73.
However, Campana, Pule and Fry are silent on a third sequence encoding an antibody fragment specific for an adenosine-producing cell surface protein CD73.
Hay teaches an anti-CD73 antibody (e.g., MEDI9447) for reducing tumor-mediated immunosuppression (abstract). Hay teaches CD73 is anchored to the cell membrane and plays a role in conversion of extracellular 5'-AMP to adenosine ([0003]), thus teaches CD73 is an adenosine-producing cell surface protein in claims 2 and 4. Hay teaches CD73 generates an immunosuppressed environment by increasing adenosine levels, which promote the development and progression of cancer ([0004]). Hay teaches anti-CD73 antibody MEDI9447 can internalize CD73 on tumor cells (Example 4, [0344]) and inhibit conversion of AMP to adenosine in cancer cells in a dose-dependent manner (Example 5, [0349-0350] and Fig 3). Hay teaches anti-CD73 antibody can be used in treating cancer such as sarcoma (e.g., [0010]).
Wang summarizes adenosinergic signaling (e.g., through CD73) as a target for natural killer cell immunotherapy of cancer (abstract). Wang teaches “one human CD73 antibody has progressed to clinical trials, Medimmune’s MEDI9447” (the anti-CD73 antibody taught by Hay), and teaches anti-CD73 antibody inhibits tumor growth by recruitment of NK cells and enhances the lytic ability of NK cells against cancer cells by a combination of antibody-dependent cellular cytotoxicity (ADCC) as well as a reduction in the rate of adenosine accumulation due to inhibition of CD73 catalytic activity (p. 908, right col, para 3).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the NK cells engineered with the polynucleotide construct comprising an NKG2D CAR operably linked to an anti-GD2 CAR for treating cancer such as sarcoma suggested by Campana, Pule and Fry, by combining a third sequence encoding an anti-CD73 antibody taught by Hay with a reasonable expectation of success. Since Campana and Pule suggest an NK cell engineered with the polynucleotide construct comprising two CARs for treating cancer such as sarcoma (see above), and since Hay teaches an anti-CD73 antibody such as MEDI9447 can reduce tumor-mediated immunosuppression in a tumor environment by reducing adenosine in cancer cells (abstract, [0003-0004] and Example 5, [0349-0350]) and can be used in treating cancer such as sarcoma (e.g., [0010]), and since Wang summarizes an anti-CD73 antibody inhibits tumor growth by recruiting NK cells and enhancing the lytic ability of NK cells against cancer cells by a combination of ADCC as well as a reduction in adenosine accumulation (p. 908, right col, para 3), one of ordinary skill in the art would have had a reason to combine an anti-CD73 antibody of Hay with the NK cells engineered with two CARs of Campana, Pule and Fry in order to reduce immunosuppression and to enhance the cytolytic activity of NK cells for treating a cancer such as sarcoma.
In regard to combing the third sequence encoding an anti-CD73 antibody with the first and second sequences within a single polynucleotide construct that further comprises a cleavable linker, as stated supra, Fry teaches a bicistronic polynucleotide construct that may comprise multiple CARs (e.g., three) wherein each CAR is separated by a cleavable domain ([0052]). Thus, Fry provides a polynucleotide construct that may comprise a first sequence (encoding an NKG2D chimeric receptor of Campana), a second sequence (encoding an anti-GD2 CAR of Pule) and a third sequence (encoding an anti-CD73 antibody of Hay). As stated supra, Hay investigates different combinatory therapies and concludes that the bicistronic (or multicistronic) polynucleotide construct functions superior over other systems (see discussion above).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the combinatory CAR-NK therapy and anti-CD73 antibody for treating a cancer such as sarcoma suggested by Campana in view of Pule, Fry, Hay and Wang, by choosing a bicistronic (multicistronic) construct comprising a single polynucleotide construct comprising multiple sequences each operably linked through a cleavable domain as taught by Fry with a reasonable expectation of success. Since Fry investigates and teaches a bicistronic (multicistronic) construct achieves superior therapeutic results over other combinatory systems (see [0268 and 0273-0275]), one of ordinary skill in the art would have had a reason to choose the multicistronic construct of Fry to express the anti-CD73 antibody of Hay in the same single polynucleotide construct comprising the two CARs of Campana in view of Pule and Fry in order to obtain an equal expression of the sequences to achieve superior therapeutic results.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Campana et al., (US Patent No. 9,511,092) in view of Pule et al., (US 2017/0066838) and Fry et al., (WO 2018/213337), as applied to claims 1 and 19 above, and further in view of alignment (sequence alignment between prior arts and instant sequences of SEQ ID NOs: 6-8, p. 1-12, attached as NPL) and Song (US 2018/0100016).
Claim 22 is examined as being directed to the first sequence encoding a first amino acid that has at least 90% sequence identity to SEQ ID NO: 6 and the second sequence encoding a second amino acid that has at least 90% sequence identity to SEQ ID NO: 7, as discussed in the 112(d) rejection above.
In regard to the first sequence encoding a first amino acid that has at least 90% sequence identity to SEQ ID NO: 6, as stated supra, Campana teaches a chimeric receptor comprising NKG2D, DAP10 and CD3 zeta (e.g., col. 2, para “Brief Summary”), wherein the CD3 zeta cytoplasmic domain comprises the amino acid sequence of SEQ ID NO: 10, the NKG2D receptor comprises the amino acid sequence of SEQ ID NO: 12 (Campana claim 8). Figure 1A (attached below) shows the structure of the NKG2D CAR arranged as CD3zeta-NKG2D-DAP10-FLAG tag (it is noted that Campana’s DAP10 contains a FLAG tag and DAP-FLAG has a sequence in Campana SEQ ID NO: 18).
PNG
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Greyscale
Thus, Campana’s construct has a sequence encoding an amino acid sequence of Campana SEQ ID NOs: 10-12-18 (see alignment p. 1) that has at least 90% sequence identity to instant SEQ ID NO: 6 (94% identical, see alignment p. 2-3).
In regard to the second sequence encoding a second amino acid that has at least 90% sequence identity to SEQ ID NO: 7, as stated supra, Pule teaches a polynucleotide construct encoding an anti-GD2 CAR. Pule teaches one of the anti-GD2 CARs has an antigen-binding domain scFv derived from the anti-GD2 14g2a clone antibody (which is a gold standard as it is used as a therapeutic antibody, see [0044]) and an intracellular signaling domain containing CD28-CD3 zeta (14g2a-28-Z, see Fig 14a second row, the intracellular domain of CD28-CD3z has a sequence of SEQ ID NO: 17 [0097]). Pule teaches the CAR has a transmembrane domain comprising the sequence shown as SEQ ID NO: 13 ([0094]), and a spacer sequence to connect the GD2-binding domain with the transmembrane domain, an exemplary spacer being human CD8 stalker with SEQ ID NO: 21 ([0108-0111]). Figure 5a of Pule shows the structure of the CAR arranged as VL-linker-VH-spacer-transmembrane-intracellular domain. Furthermore, Song teaches the VL sequence (Song SEQ ID NO: 16, [0052]) and VH sequence (Song SEQ ID NO: 14, [0050]) of the anti-GD2 14g2a clone antibody and a linker sequence of Song SEQ ID NO: 15 ([0051]), that is used in generating an anti-GD2 CAR NK cell (abstract).
Thus, Pule’s anti-GD2 CAR construct (14g2a-28-Z) has a sequence encoding an amino acid sequence of VL (Song SEQ ID NO: 16) – linker (Song SEQ ID NO: 15) – VH (Song SEQ ID NO: 14) - spacer (Pule SEQ ID NO: 21) – transmembrane (Pule SEQ ID NO: 13) – intracellular domain (Pule SEQ ID NO: 17) (alignment p. 4-5) that has at least 90% sequence identity to instant SEQ ID NO: 7 (93% identical, see alignment p. 6-7).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the polynucleotide construct comprising a first sequence encoding an NKG2D chimeric receptor and a second sequence encoding an anti-GD2 CAR suggested by Campana in view of Pule and Fry, by choosing the first sequence encoding a first amino acid that has at least 90% sequence identity to SEQ ID NO: 6 and the second sequence encoding a second amino acid that has at least 90% sequence identity to SEQ ID NO: 7 as taught by Campana, Pule and Song with a reasonable expectation of success. Since Campana reduces to practice a functional NKG2D chimeric receptor having an amino acid sequence that has at least 90% identity to SEQ ID NO: 6, and since Pule and Song reduces to practice an anti-GD2 CAR having an amino acid sequence that has at least 90% identity to SEQ ID NO: 7 and teaches the anti-GD2 14g2a clone antibody is a gold standard as it is used as a therapeutic antibody and has been tested in a CAR, and the second generation CAR format is the most widely used CAR format in clinical studies (Pule, [0044]), one of ordinary skill in the art would have had a reason to choose the sequences taught by Campana, Pule and Song in order to use the tested sequences in the polynucleotide construct to transduce an immune cell for treating a cancer.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Campana et al., (US Patent No. 9,511,092) in view of Pule et al., (US 2017/0066838) and Fry et al., (WO 2018/213337), as applied to claims 1 and 23 above, and further in view of Hay et al., (US 2016/0129108), Wang et al., (J Mol Med. 2018 August 1; 96: 903-913), alignment (sequence alignment between prior arts and instant sequences of SEQ ID NOs: 6-8, p. 1-12, attached as NPL) and Song (US 2018/0100016).
Claim 24 is directed to the engineered cell expressing an amino acid sequence that has at least a 90% sequence identity to SEQ ID NO: 8.
As stated supra, Campana in view of Pule and Fry suggests an engineered cell that expresses the polynucleotide construct according to claim 1.
However, Campana, Pule and Fry are silent on a third sequence encoding an antibody fragment specific for CD73.
Hay, Wang and Fry make obvious a combination of a sequence encoding an anti-CD73 antibody in the polynucleotide construct according to claim 1 for the same reason set forth in the rejection of claims 2 and 4 (see above) and omitted for the sake of concise prosecution.
In regard to the first sequence and the second sequence encoding a first and a second amino acid sequences having at least a 90% sequence identity to SEQ ID NOs: 6 or 7, Campana, Pule and Song make obvious a first and a second amino acid sequences that have at least a 90% sequence identity to SEQ ID NOs: 6 or 7, respectively, for the same reason set forth in the rejection of claim 22 (see above) and omitted for the sake of concise prosecution.
In regard to the third sequence encoding an anti-CD73 antibody, as stated supra, Hay teaches an anti-CD73 antibody (e.g., MEDI9447) for reducing tumor-mediated immunosuppression (abstract) and teaches the sequences of MEDI9447 VH shown in Hay SEQ ID NO: 21 ([0013], see Fig 1A) and MEDI9447 VL shown in Hay SEQ ID NO: 23 ([0014], see Fig 1B). Wang teaches “one human CD73 antibody has progressed to clinical trials, Medimmune’s MEDI9447” (p. 908, right col, para 3). Thus, Hay teaches an MEDI9447 clone of anti-CD73 antibody having an amino acid sequence of Hay SEQ ID NO: 21 – Hay SEQ ID NO: 23.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have chosen the amino acid sequence of the MEDI9447 clone of anti-CD73 antibody as taught by Hay with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to choose this sequence since Hay has reduced to practice the sequence of a functional anti-CD73 antibody and since Wang teaches this clone of anti-CD73 antibody has progressed to clinical trials that facilitates future application in treating cancer.
Furthermore, one of ordinary skill in the art would have appreciated that in a single polynucleotide construct comprising three sequences, there are a limited number of arrangement (3x2x1=6). Thus, one of ordinary skill in the art would have immediately envisioned an option of arrangement as anti-CD73 antibody – anti-GD2 CAR – NKG2D CAR each linked by a cleavable linker comprising a P2A (see Fry [0071] and Constructs #V5-V8 in Fig 1, the P2A has the sequence of Fry SEQ ID NO: 39 (e.g., p, 19, Table 3, 2nd row from last)). It is noted that the amino acid sequence of this arrangement (see alignment p. 8-9) has at least a 90% sequence identity to SEQ ID NO: 8 (91% identity, see alignment p. 10-12).
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Conclusion
No claims are allowed.
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/JIANJIAN ZHU/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631