DETAILED ACTION
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 .
Status of Claims
Claims 1-3, 5, 6, 8, 17, 20, 21, 23, 27, 36, 37, 66, 68 and 81-85 are pending.
Claims 3, 5, 6, 8, 17, 20, 21, 23, 27, 36, 66 and 81-85 are amended.
Claims 1-3, 5, 6, 8, 17, 20, 21, 23, 27, 36, 37, 66, 68 and 81-85 are currently under examination on the merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The U.S. effective filing date of all claims under examination is set at 10/22/2020 based on the provisional application 63/104,419 (filed 10/22/2020).
Specification
The disclosure is objected to because of the following informalities:
In Paragraphs [0044] and [0045] on Pg. 11, there appears to be typographical errors in these two paragraphs. The last sentences in these two paragraphs appear to be incomplete because they recite "…..target cells as ."
In Paragraph [0227] line 4 on Pg. 64, there appears to be a typographical error. The sentence is missing the symbol for degrees for the phrase “37C”.
Appropriate correction is required.
Claim Objections
Claims 1, 3, 37 and 68 are objected to because of the following informalities:
Claim 1 is objected to because of a typographical error in line 3. The word “and” should be amended to be placed before “(iii)” so that line 3 recites “…transmembrane domain; and (iii) a CD2 costimulatory domain;…..”
Claim 3 is objected to because of a typographical error in line 4. For consistency, “TGFb” should be replaced with “TGFβ”.
Claim 37 is objected to because of a typographical error in line 2. The word “and” should be amended to be placed before “(iii)” so that lines 2-3 recite “…(ii) a transmembrane domain; and (iii) a CD2 costimulatory domain.”
Claim 68 is objected to because of a typographical error in line 2. The word “and” should be amended to be placed before “(iii)” so that line 2 recite “…(ii) a transmembrane domain; and (iii) a CD2 costimulatory domain.”
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 6 and 8 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AlA), 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-AlA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 6 (i), (ii) and (iii), and claim 8 (i), (ii), (iii) and (iv) recite the term "TGFβRII-binding domain". This term can be read and interpreted as a domain that binds to TGFβRII, not a domain of TGFβRII that binds TGFβ. The term can also be read and interpreted as a domain of TGFβRII that binds to TGFβ. Therefore, the metes-and-bounds of the claims are unclear because it is unclear whether the claims are to read on a binding domain fused to CD28 costimulatory domain wherein the binding domain binds to TGFβRII or whether the claims are to read on a domain of TGFβRII that binds to TGFβ fused to CD28 costimulatory domain. It is unclear which construct is to be used in the comparison against the construct of the TGFβ-binding domain fused to a CD2 costimulatory domain as recited in claim 1.
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.
Claim(s) 1, 2, 3, 5, 6, 8, 17, 20, 21, 23, 27, 36, 37, 66, 68 and 81-85 are rejected under 35 U.S.C. 103 as being unpatentable over Posey et al. (US20200306304A1 Date Published 2020-10-01) in view of UnitProtKB (P37173 · TGFR2_HUMAN; Last updated 2006-10-17 v2), Oh et al. (J Immunol. 2013 Oct 15;191(8):3973-90), Posey and June (Molecular Therapy Volume 23, Supplement 1, May 2015, Page S83) and Velapasamy et al. (Cancers 2018, 10, 247).
Posey et al. teaches a modified immune cell comprising a chimeric antigen receptor (CAR) that specifically binds to TnMUC1, nucleic acids encoding said CAR, and methods of treating cancer in a subject in need thereof (Abstract). Posey et al. also teaches the modified immune cell further comprises a dominant negative receptor wherein the dominant negative receptor is a truncated dominant negative variant of a wild-type TGF-β receptor type II (TGF-βRII-DN) associated with a negative signal comprising the amino acid sequence set forth in SEQ ID NO:76 or variants thereof that maintain intended function with at least 60% identity (201 amino acids; Paragraphs [0014]-[0016], [0255], [0256] and Table 1).
Posey et al. teaches the modified immune cell can also further comprise a switch receptor wherein the switch receptor comprises: (i) a domain comprising at least a portion of an extracellular domain of a TGFβR that is associated with a negative signal, (ii) a transmembrane domain, and (iii) a domain comprising at least a portion of an intracellular domain of IL12Rβ2 that is associated with a positive signal, and wherein the switch receptor comprises the amino acid sequence set forth in SEQ ID NO: 90, or variants thereof that maintain intended biological activity of converting a negative TGF-β signal into a positive IL-12 signal when expressed in a cell (Paragraphs [0016], [0028], [0269]-[0270] and Table 1). Posey et al. also teaches that the switch receptor transmembrane domain can comprise the transmembrane domain of TGF-βRII (which is the first polypeptide that is associated with a negative signal; Paragraph [0016]).
Sequence alignment of the dominant negative receptor of SEQ ID NO: 76 (TGF-βRII-DN) and the switch receptor of SEQ ID NO: 90 (TGFβR-IL12Rβ2) both taught by Posey et al. show that the switch receptor residues 1 to 186 matches exactly to the amino acid residues 1 to 186 of TGF-βRII-DN SEQ ID NO: 76. Therefore, Posey et al. teaches a modified immune cell that comprises a switch receptor comprising the dominant negative receptor of TGF-β receptor type II (TGF-βRII-DN) that corresponds to the extracellular domain portion of the receptor that can bind TGF-β, a negative signal transduction molecule present in tumor microenvironments, such that binding of TGF-β to TGF-βRII-DN on the modified immune cell can reduce the inhibitory and immunosuppressive effects TGF-β have on the modified immune cell (Paragraphs [0252] and [0254]).
Alignment of SEQ ID NO: 76 (TGF-βRII-DN; top) and SEQ ID NO: 90 (TGFβR-IL12Rβ2; bottom) taught by Posey et al.
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The sequence alignment of the switch receptor of SEQ ID NO: 90 (403 amino acids) comprising the TGF-βRII-DN as taught by Posey et al. and that of instant SEQ ID NO: 6 which sets forth the amino acid sequence for the instant TGFβ-binding domain (144 amino acids in instant claim 17) shows that instant SEQ ID NO: 6 is fully comprised within amino acid residues 23 to 166 of SEQ ID NO: 90 taught by Posey et al. Therefore, Posey et al. teaches an immune cell comprising a receptor that comprises an extracellular domain of TGFβRII that is a TGFβ-binding domain comprising the amino acid sequence as set forth in instant SEQ ID NO: 6. The sequence of human TGF-beta receptor type-2 provided by UnitProtKB (P37173 · TGFR2_HUMAN) was also aligned with instant SEQ ID NO: 6 (data not shown) and is fully comprised within amino acid residues 23 to 166 of human TGF-beta receptor type-2 (567 amino acids). Since instant SEQ ID NO: 6 is also fully encompassed within SEQ ID NO: 90 of Posey et al. from residues 23 to 166, this means that Posey et al. teaches a receptor that is part of the extracellular domain of the human TGF-beta receptor type-2.
Alignment of instant SEQ ID NO: 6 (TGFβ-binding domain; top) and SEQ ID NO: 90 (TGFβR-IL12Rβ2; bottom) taught by Posey et al.
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Posey et al. teaches that the immune cell also known as a host cell, is a T cell, a regulatory T cell (Treg), a natural killer (NK) cell, a natural killer T (NKT) cell, a stem cell, or an induced pluripotent stem cell isolated from a subject (Paragraph [0274], [0327, [0359] and [0360]). They teach an expression construct comprising the isolated nucleic acid of the switch receptor comprising the amino acid sequence as set forth in SEQ ID NO: 90 (Paragraph [0052] and [0298]). They also teach that the expression construct can further comprise an EF-1α promoter, a rev response element (RRE), a woodchuck hepatitis virus posttranscriptional regulatory element (WPRE) or a cPPT sequence, or a combination thereof as regulatory sequences (Paragraph [0052]). They further teach that the expression construct is a viral vector (Paragraphs [0053] and [0313]).
Posey et al. teaches pharmaceutical compositions comprising the modified immune cell in combination with one or more pharmaceutically or physiologically acceptable carriers, diluents or excipients (Paragraph [0562]). Posey et al. also teaches the modified immune cells comprising a switch receptor, may be prepared or produced by stably transfecting host cells with an expression vector encoding said nucleic acid (Paragraph [0328]). Posey et al. further teaches that the modified T cells, after being transfected with and therefore comprising the switch receptor comprised of the dominant negative receptor TGFβRII-DN and IL12Rβ2, is capable of converting the inhibitory TGF-β from the tumor microenvironment into a positive signal (Paragraphs [0253], [0254] and [0281]), thereby converting an endogenous TGFβR activity to a stimulatory signal as well as modulating the TGFβ activity in a tumor microenvironment. They also teach a method of treating cancers comprising administering to the subject in need thereof, a modified immune cell comprising a switch receptor (Paragraphs [0403]-[0406]).
Posey et al. does not specifically teach an immune cell comprising a chimeric activation receptor (defined as a switch receptor by Posey et al.), wherein the receptor comprises a CD2 costimulatory domain, or wherein the CD2 costimulatory domain comprises an amino acid sequence having at least about 70% sequence identity to the amino acid sequence set forth in instant SEQ ID NO: 7. Posey et al. also do not specifically teach a nucleic acid encoding a chimeric activation receptor comprising a CD2 costimulatory domain.
Posey et al. also does not specifically teach wherein the immune cell expresses an endogenous TGFβRI and/or TGFβRII.
Posey et al. also does not specifically teach the immune cell, wherein upon interaction of the chimeric activation receptor with TGFβ, the immune cell: (i) produces one or more cytokines at a higher level than a cell expressing a TGFβ-binding domain fused to a CD28 costimulatory domain upon interaction with TGFβ; (ii) is more proliferative than a cell comprising a TGFβ-binding domain fused to a CD28 costimulatory domain upon interaction with TGFβ; (iii) has increased cytolytic activity as compared to a cell comprising a TGFβ-binding domain fused to a CD28 costimulatory domain upon binding to TGFβ; or (iii) any combination of (i)-(iii).
Posey et al. further does not specifically teach a chimeric activation receptor, wherein the receptor comprises a transmembrane domain that comprises an amino acid sequence having at least about 70% sequence identity to the amino acid sequence set forth in instant SEQ ID NO: 8.
Posey et al. also further does not specifically teach the immune cell, wherein upon the interaction with TGFβ, the immune cell: (i) expresses IL2 at a level that is at least about 125% the expression of IL2 by a cell expressing a TGFβ-binding domain fused to a CD28 costimulatory domain upon binding to TGFP; (ii) expresses IFNϒ at a level that is at least about 125% the expression of IFNϒ by a cell expressing a TGFβ-binding domain fused to a CD28 costimulatory domain upon binding to TGFβ; (iii) is at least about 25% more proliferative than a cell comprising a TGFβ-binding domain fused to a CD28 costimulatory domain upon interaction with TGFβ; (iv) has a cytolytic activity that is at least about 125% the cytolytic activity of a cell comprising a TGFβ-binding domain fused to a CD28 costimulatory domain upon interaction with TGFβ; or (v) any combination of (i)-(iv).
However, these deficiencies are made up in the teachings of Posey et al., Oh et al. and Posey and June.
Posey et al. teaches a CAR that comprises a costimulatory signaling domain wherein the costimulatory signaling domain is a CD2 costimulatory signaling domain comprising the amino acid sequence set forth in SEQ ID NO: 28 (Paragraphs [0006], [0010], [0038] and [0409]). Posey et al. also teaches that a “co-stimulatory signal”, refers to a signal which leads to T cell proliferation (Paragraph [0120]).
Sequence alignment of the CD2 costimulatory signaling domain comprising the amino acid sequence set forth in SEQ ID NO: 28 taught by Posey et al. and that of instant SEQ ID NO: 7 (116 amino acids) which sets forth the amino acid sequence for instant CD2 costimulatory domain shows that instant SEQ ID NO: 7 exactly matches amino acid residues 2 to 117 of SEQ ID NO: 28 taught by Posey et al (see below). Therefore, Posey et al. teaches an immune cell comprising a receptor that comprises a CD2 costimulatory domain comprising the amino acid sequence as set forth in instant SEQ ID NO: 7.
Alignment of instant SEQ ID NO: 7 (CD2 costimulatory domain; top) and SEQ ID NO: 28 (CD2 costimulatory domain; bottom) taught by Posey et al.
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Posey et al. teaches a CAR that comprises a transmembrane domain wherein the transmembrane domain comprises a CD8α transmembrane domain comprising the amino acid sequence as set forth in SEQ ID NO: 7 (Paragraphs [0006], [0009] and [0216]). Sequence alignment of the CD8α transmembrane domain comprising the amino acid sequence set forth in SEQ ID NO: 7 taught by Posey et al. and that of instant SEQ ID NO: 8 which sets forth the amino acid sequence for instant transmembrane domain shows that instant SEQ ID NO: 8 exactly matches SEQ ID NO: 7 from Posey et al. Therefore, Posey et al. teaches an immune cell comprising a receptor that comprises a CD8α transmembrane domain comprising the amino acid sequence as set forth in instant SEQ ID NO: 8 (alignment not shown for the reference and instant transmembrane domains where both consist of 24 amino acid residues).
Oh et al. teaches that TGF-β is an important guardian and regulator of T cell function (Title, Abstract and Figure 1). Oh et al. also teaches that TGF-β is activated to allow for engagement of a tetrameric receptor complex composed of TGF-β receptors I and II (TGF-βRI and TGF-βRII) present on immune cells (Pg. 1Paragraphs 1 and 2). They teach on Pg. 2 TGF-βRII in CD8+ T cells (Paragraph 2), on Pg. 2 TGF-βRI in tTreg cells (Paragraph 3), on Pg. 3 TGF-βRII in CD4+ T cells (Paragraph 4), on Pg. 4 TGF-βRII in CD8+ T cells (Paragraph 1), and on Pg 6 that tTreg and iNKT cells express TGF-βRII (Paragraph spanning). Therefore, Oh et al. teaches that immune cells, including T cells and iNKT cells, express endogenous TGF-βRI and TGF-βRII that are receptors that bind to TGF-β. As such, the T cells isolated from a subject as taught by Posey et al. in Paragraph [0359] would express endogenous TGF-βRI and TGF-βRII.
Posey and June teach an anti-mesothelin (SS1) chimeric antigen receptor known as SS1CD2z that comprises co-stimulatory endodomain of CD2 juxtaposed to CD3z (abbreviated to z) activation domain (Lines 11-13). Posey and June also teach that human T cells modified with SS1CD2z demonstrate comparable cytotoxicity of tumor cell lines in vitro as SS1z, SS1BBz (where BB is the abbreviation for 4-1BB costimulatory domain), and SS128z (where 28 is the abbreviation for CD28 costimulatory domain) (lines 13-16). Posey and June further teach that Luminex analysis revealed that IL-2 production is superior among SS128z and SS1CD2z, while SS1BBz T cells produced less IL-2, all CAR cells produced comparable IFNγ levels, and SS1CD2z cells produced minimal quantities of TNFα similar to SS1BBz cells; contrary to SS128z cells, which produce large quantities of the neurotoxic cytokine (lines 21-26). They also teach that SS1CD2z T cells exhibited a fast and durable anti-tumor response against a subcutaneous mesothelioma xenograft model, while both SS128z and SS1BBz T cells lagged in terms of response rate, suggesting that CAR co-stimulation via CD2 can produce potent antitumor activity, enhanced T cell proliferation and favorable cytokine profiles compared to co-stimulation via CD28 (lines 26-31). Therefore, Posey and June teach that including a CD2 costimulatory domain in a CAR has advantages compared to one that includes a CD28 costimulatory domain in terms of cytokine production such as IL2, T cell proliferation, and tumor cell cytotoxicity.
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of making and using an immune cell comprising a “switch” receptor that comprises the extracellular domain of TGFβRII (a TGFβ-binding domain), a transmembrane domain of TGFβRII and an intracellular domain of IL12Rβ2 (SEQ ID NO: 90) as taught by Posey et al. and substituting the IL12Rβ2 intracellular domain taught by Posey et al. with the CD2 costimulatory domain of SEQ ID NO: 28 also as taught by Posey et al. and/or substituting the transmembrane domain of TGFβRII taught by Posey et al. with the CD8α transmembrane domain of SEQ ID NO: 7 also as taught by Posey et al. because Posey et al. teaches that immune cells comprising a receptor that can “switch” or convert the negative signal of TGFβ into a positive signal through binding to a dominant negative receptor of TGFβRII fused to an intracellular domain associated with a positive signal are capable of enhancing the effectiveness of CAR-T cell therapy in the “limiting and immunosuppressive microenvironment” of tumor cells (Paragraphs [0253] and [0254]). In addition, Posey et al. also teaches advantages of the combined method of making said receptor include potent cytotoxicity against target tumor cell lines exhibited by an immune cell comprising a CAR receptor constructed with a CD2 costimulatory domain (5E5-CD2z CAR T; Paragraph [0634]), and impeded tumor growth and cytotoxicity against target tumor cells upon culture with immune cells comprising a CAR constructed with a CD8 transmembrane domain (CART-TnMUC1; (Paragraph [0629]). In addition, Posey and June teaches that the CD2 costimulatory domain demonstrated enhanced activity compared to CD28 costimulatory domain when expressed in a CAR T cell, resulting in superior IL-2 production, comparable T cell proliferation and potent antitumor activity (Title and lines 4-6, 16, 22 and 26-31). This is an example of (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
With regards to claim 1, since Posey et al teaches that the immune cells are isolated from subjects and include T cells, and since Oh et al. teaches that T cells comprise TGF-βRI and TGF-βRII that are crucial for regulation by TFGβ, it is therefore obvious that the immune cells isolated as taught by Posey et al. would express endogenous TGF-βRI and TGF-βRII. Further, when such isolated T cells are modified by transfecting with an expression vector that comprises an extracellular domain of TGF-βRII and a transmembrane domain of TGF-βRII as taught by Posey et al., further comprising the positive signaling domain of the CD2 costimulatory domain of SEQ ID NO: 28 also as taught by Posey et al., the resultant modified T cells would comprise a chimeric activation or “switch” receptor that comprises (i) a transforming growth factor β (TGF β)-binding domain; (ii) a transmembrane domain; and (iii) a CD2 costimulatory domain; wherein the immune cell expresses an endogenous TGFβRI and/or TGFβRII.
With regards to claim 3, wherein the chimeric activation receptor is capable of forming a heteroteradimer with endogenous TGF-βRI and/or TGF-βRII, since Oh et al. teaches that TGF-β receptors when bound to TGF-β, forms a tetrameric receptor complex composed of TGF-β receptors I and II, therefore the chimeric activation or “switch” receptor comprising the extracellular domain of TGF-βRII as taught by Posey et al. would inherently be capable of forming a heterotetradimer with endogenous TGFβRI and TGFβRII. The teachings of Velapasamy et al. further corroborates the ability of the chimeric activation receptor rendered obvious to form such a tetrameric complex by teaching in Figure 1 that when two activated TGFβ binds to two TGFRβII on the extracellular surface of a cell, the interaction induces the two TGFRβII to recruit and activate two other TGFβRI present on the cell surface (Pg. 2 of 23).
With regards to claim 6, although Posey et al. and Posey and June do not specifically teach the immune cell comprising the chimeric activation receptor rendered obvious, upon interaction with TGFβ, produces cytokines at higher levels, or is more proliferative than, or has increased cytolytic activity compared to just any imaginable cell expressing just any TGFβ-binding domain fused to a CD28 costimulatory domain upon interaction with TGFβ, one would still be motivated to generate the immune cells for the reasons stated above and the recited increased activity using the CD2 domain as compared to constructs with the CD28 domain is predictable because Posey and June teaches that SS1CD2z T cells demonstrated more effective activity over SS128z T cells in terms of IL2 production, proliferation and anti-tumor activity (Posey and June, Title and lines 4-6, 16, 22 and 26-31, and as discussed above in Pg. 13-14). The office does not have the facilities and resources to provide the factual evidence needed in order to establish that the product rendered obvious does not possess the same characteristics as the claimed product. See In re Best 562F .2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2nd 1992 (PTO Bd. Pat. App. & Int. 1989).
With regards to claim 8, although Posey et al. and Posey and June do not specifically teach the immune cell comprising the chimeric activation receptor rendered obvious, upon interaction with TGFβ, (i) expresses IL2 at a level that is at least about 125%; (ii) expresses IFNy at a level that is at least about 125%; (iii) is at least about 25% more proliferative; (iv) has a cytolytic activity that is at least about 125%; when compared to just any imaginable cell expressing just any TGFβ-binding domain fused to a CD28 costimulatory domain upon interaction with TGFβ, one would still be motivated to generate the immune cells for the reasons stated above and the recited increased activity using the CD2 domain as compared to constructs with the CD28 domain is predictable because Posey and June teaches that SS1CD2z T cells demonstrated more effective activity over SS128z T cells in terms of IL2 production, proliferation and anti-tumor activity (Posey and June, Title and lines 4-6, 16, 22 and 26-31, and as discussed above in Pg. 13-14). The office does not have the facilities and resources to provide the factual evidence needed in order to establish that the product rendered obvious does not possess the same characteristics as the claimed product. See In re Best 562F .2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2nd 1992 (PTO Bd. Pat. App. & Int. 1989).
Taken all together, the combination of art above clearly renders the claimed inventions above as a whole prima facie obvious.
Conclusion
No claims are allowed.
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/YIE-CHIA LEE (TONYA)/Examiner, Art Unit 1642
/SEAN E AEDER/Primary Examiner, Art Unit 1642