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 .
Claims status
Applicants reply filed 3/31/2026 is acknowledged.
Claims 43, 47, 60-62, 72, 73, 76, 78-87 is/are cancelled and claims 88-106 is/are newly added. Claims 42, 44, 48, 88-106 is/are currently pending and is/are under examination.
Specification – Maintained
The use of the terms Opti-MEM, PLUS, LTX, GlutaMAX, ImmunoCult, CliniMACS, TexMACS, TransAct, which are trade names or marks 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.
Applicant’s reply filed 3/31/2026 did not address this objection to the specification however since the response filed is deemed a bona fide attempt to advance the application to final action and contains this minor deficiency of failing to respond this objection, it is reiterated here (see MPEP 714.03).
Claim Rejections - 35 USC § 112(b) – New, necessitated by claim amendments
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.
Rejection of Claims 44 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in light of claim amendment.
Claims 42, 44, 48, 88-93, 104 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 42 is directed to a T-cell genetically modified to express any one or more of the recited recombinant arginine transporters. Claim 42 is amended to recite “wherein [..] T-cell has been primed in a media comprising arginine, thereby to increase the intracellular arginine level” (emphasis added). It is unclear what structure is provided to the product of claim 42 by this newly added limitation. Although the claim recites that the claimed T-cell has been primed in the said media, it is clear that the T-cell is not in said media such that it could be interpreted that the claim is directed to the recited cell in the recited media. Further, it is clear that priming was for the purpose of increasing the intracellular arginine level. However it is unclear if the T-cell indeed has a structure of “increased intracellular arginine level” and if so, to what extent and for what duration. The specification does not measure intracellular arginine levels in any genetically-modified T-cell for any duration. Thus there is no guidance if the claimed genetically modified T-cells with any of the recited transporters have increased arginine levels after being primed in a media that comprises any amount of arginine and if so, to what level. For the purpose of compact prosecution, the claim(s) 42 is/are interpreted as T-cell genetically modified to express any one or more of the recited recombinant arginine transporters that is capable of increase in intracellular arginine at any level for any duration.
Claim 91 recites the limitation "CAT-2 isoform" in line 2. There is insufficient antecedent basis for this limitation in the claim. For the purpose of compact prosecution, the claim(s) 91 is/are interpreted as "wherein the one or more exogenous recombinant arginine transporter is CAT-2 and wherein the CAT-2 is a CAT-2 isoform selected".
Claims 44, 48, 88-93 is/are rejected due their dependence on claim 42 because they do not clarify the 112b issue noted with claim 42.
Claim 104 recites the limitation "CAT-2 isoform" in line 2. There is insufficient antecedent basis for this limitation in the claim. For the purpose of compact prosecution, the claim(s) 91 is/are interpreted as "wherein the one or more exogenous recombinant arginine transporter is CAT-2 and wherein the CAT-2 is a CAT-2 isoform selected".
Claim Rejections - 35 USC § 112- Maintained for claim 44, New for amended/new claims
Rejection of Claim 43 on the basis that they contain an improper Markush grouping of alternatives is moot due to claim cancellation.
Claim 44 remains and Claim 42, 94, 96 are rejected on the basis that they contain an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
Members of a Markush group share a "single structural similarity" when they belong to the same recognized physical or chemical class or to the same art-recognized class. A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved.
The Markush grouping of CAT-1, CAT-2, CAT-3, CAT-4, y+LAT1 and 4F2hc, y+LAT2 and 4F2hc, b0,+AT and rBAT, and ATB0,+ in Claim 42 and associated nucleic acid sequences recited in claim 44 are improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
The claimed ‘arginine transporters’ belong to at least three distinct art-recognized groups of amino acid transporters that are both structurally and functionally distinct. ATB0,+ is the most distinct, belonging to the SLC6 family of amino acid transporters and is generally considered to have several unique characteristics (see Abstract in Karunakaran et al (THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 286, NO. 36, pp. 31830–31838, September 9, 2011)). Its transport function is controlled by the concentration gradient of both Na+ and Cl- ions while it transports nearly all essential amino acids, albeit to a low level (Introduction, para 1 and 2). This transporter is distinct from the CAT, LAT and BAT transporters recited.
Fotiadis et al (Molecular Aspects of Medicine 34 (2013) 139–158) provides a recent review of the amino acid transporters from the SLC3 and SLC7 families of amino acid transporters that cover the CAT, LAT and BAT transporters. They teach that SLC7 family of transporters comprise two distinct families: Cationic amino acid transporters (CATs; CAT1-4) and the L-type amino acid transporters (LATs; y+LAT1, 2) (Introduction, para 1). These two groups are structurally and functionally distinct. While CATs are homomeric transmembrane proteins, LATs form heteromers (i.e. Heteromeric Amino acid transporters, HATs) with subunits from the SLC3 family (4F2hc, rBAT) and require these heteromeric structure to function (see exemplar structural difference in Figure 1, Introduction, para 1). Furthermore, while CATs are facilitated transporters for cationic amino acids, in contrast HATs are exchangers for a wide spectrum of amino acids (Introduction, paras 2-3; Table 1). Thus, the group, as a whole, does not share a substantial structural feature and a common use that flows from the substantial structural feature such that “single structural similarity” could be recognized.
Critically, there is an no expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention i.e. as arginine transporters that when expressed in T-cells would increase arginine concentration in the T cell.
For example, even within the CAT family of transporters, functional differences were known amongst CAT4 and CAT1-3 transporters. CAT4 is considered an orphan transporter because it appears to not transport amino acids (See 2.4. CAT-4 (SLC7A4) and SLC7A14 in Fotiadis).
Similarly, substrate selectivity and ion coupling differ among LATs/HATs and “Thus, these transporters correspond to system L (4F2hc/LAT1 and 4F2hc/LAT2), system y+L (4F2hc/y+LAT1 and 4F2hc/y+LAT2), system xc- (4F2hc/xCT), system asc (4F2hc/Asc-1 and Asc-2 linked to an unknown heavy subunit) and system b0,+ (rBAT/b0,+AT)” (See 4. HATs and their light subunits in Fotiadis). Thus, the group, as a whole, could not be considered to belong to an art-recognized class that were considered functionally equivalent resulting in a common use.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 101 – Maintained, New for new claims
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Rejection of Claims 43 under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more is moot due to claim cancellation.
Claims 42, 44, 48, 94-100 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
A three-part inquiry has been established to determine subject matter eligibility under 35 U.S.C. 101 for process claims that involve laws of nature. See Subject Matter Eligibility Guidance in MPEP 2106. This inquiry comprises answering: 1) Is the claimed invention directed to one of the four statutory patent-eligible subject matter categories: process, machine, manufacture, or composition of matter? 2A) Does the claim recite or involve one or more judicial exceptions? Judicial exceptions include abstract ideas, laws of nature/natural principles, natural phenomena, and natural products. 2B) Does the claim as a whole recite something significantly more than the judicial exception(s)?
Claim Interpretation: With respect to claims 42, applicant' s invention is interpreted as comprising a T-cell that are genetically modified to express the listed transporters (CAT-1, CAT-2, CAT-3, CAT-4, y+LAT1 and 4F2hc, y+LAT2 and 4F2hc, b0,+AT and rBAT, and ATB0,+). Although claim 44 does not explicitly recites that the listed SEQ IDs are for sequences that encode transporters capable of transporting arginine, most of these sequences are disclosed as sequences for naturally occurring CAT-1, CAT-2, CAT-3, CAT-4, y+LAT1 and 4F2hc, y+LAT2 and 4F2hc, b0,+AT and rBAT, and ATB0,+ or their variants (Table 1). Therefore, claim 44 comprise T-cells that are genetically modified to expresses the specifically listed transporters capable of transporting arginine. Claim 48 is directed to a pharmaceutical composition comprising the cell of claim 42 in a pharmaceutically acceptable excipient.
Although claim 42 is amended to recite “wherein [..] T-cell has been primed in a media comprising arginine, thereby to increase the intracellular arginine level”, this limitation does not meaningfully alter the structure of the claimed genetically modified T-cell which is inherently capable of increasing intracellular arginine level to some level for at least some duration (see claim interpretation provided in the U.S.C 112b rejection above).
With respect to claims 94, similar to claim 42, applicant' s invention is interpreted as comprising a T-cell that are genetically modified to express the listed transporters (CAT-1, CAT-2, CAT-3, CAT-4, y+LAT1 and 4F2hc, y+LAT2 and 4F2hc, b0,+AT and rBAT, and ATB0,+). Claim 94 further recites “wherein the genetically modified T-cell comprises an intracellular arginine level that allows the T-cell to survive in an arginine-depleted environment.” and Claim 95 recites that “the arginine-depleted environment is a tumor microenvironment.” These limitations do not provide any additional structure to the claimed cell that is genetically modified. These additionally claimed features of the claimed cell must necessarily flow from the structure of the claimed cell and are thus inherent to a T-cell expressing the claimed transporters.
Although claim 96 does not explicitly recites that the listed SEQ IDs are for sequences that encode transporters capable of transporting arginine, most of these sequences are disclosed as sequences for naturally occurring CAT-1, CAT-2, CAT-3, CAT-4, y+LAT1 and 4F2hc, y+LAT2 and 4F2hc, b0,+AT and rBAT, and ATB0,+ or their variants (Table 1). Therefore, claim 96 comprise T-cells that are genetically modified to expresses the specifically listed transporters capable of transporting arginine.
Claims 97-100 are directed the level of intracellular arginine levels achieved in the claimed cell. These limitations do not provide any additional structure to the claimed cell that is genetically modified. These additionally claimed features of the claimed cell must necessarily flow from the structure of the claimed cell and are thus inherent to a T-cell expressing the claimed transporters.
Analysis in View of Claim Interpretation and Subject Matter Eligibility Guidance:
1) Statutory Subject Matter: Claims 42, 44, 94-100 are directed to a cell, which is a product. Claims 48 is directed to a pharmaceutical composition, which is a product . Therefore, claims 42, 44, 48, 94-100 are directed to statutory subject matter.
2) Judicial Exception Analysis:
2A) Judicial Exception
(i) Does the claim recite a judicial exception? Claim 42, 94 recite a judicial exception because it embraces nature-based products that are not markedly different from the naturally occurring counterpart. See MPEP 2106.04(c) for The Markedly Different Characteristics Analysis.
The naturally occurring counterpart of the claimed T cells that are genetically modified to expresses the claimed arginine transporters are naturally occurring T cells. Human T cells were to known express several arginine transporters and the expression of these naturally occurring arginine transporters were known to fluctuate, even increase, under conditions that occur in nature. Werner et al (Eur. J. Immunol. 2016. 46: 92–103; ref of record) show that primary human T cell express CAT1, CAT3, y+LAT1, y+LAT2, bo,+AT, ATB0,+ and that their expression changes in response to T cell stimulation (Figure 2). Werner also show that once stimulated, T-cells overexpress certain arginine transporters such that they are capable of arginine uptake even in arginine depleted environments (Figure 1) allowing them to not only survive but proliferate in such environments (Figure 6). The claimed T cells has the same phenotypic characteristics as the naturally occurring T cells such that the claimed cells would be indistinct from their naturally occurring counterparts. Although the claim recites “a recombinant arginine transporter”, no structure is recited such that a recombinant arginine transporter is distinct from a naturally occurring arginine transporter. Similarly, although the claim recites that T cell is “genetically modified to express” the transporter, no modification or structure is recited for the T cell such that the claimed T cell is structurally distinct from a naturally occurring T cell. Thus, to the extent that claim 42 and 94 recite CAT1, CAT3, y+LAT1, y+LAT2, bo,+AT, ATB0,+ as arginine transporters expressed in the claimed T cell, these are directed to a judicial exception since T cells naturally express these transporters and their expression increases under naturally-occurring conditions.
Sequences recited in claims 44 and 96 that correspond with naturally occurring sequences of CAT1, CAT3, y+LAT1, y+LAT2, bo,+AT, ATB0,+ also result in the claim 44 and 96 embracing cells that are not markedly different from the naturally occurring T cells and thus reciting a judicial exception (SEQ ID NO: 180, 204, 205, 214, 215, 220-222, 227-230, 234-236, 242, and 246).
Claim 48 recited the T cell of claim 42 in a pharmaceutical composition that additionally comprises a “pharmaceutically acceptable excipient” however does not recite any specific excipient. As such, some pharmaceutically acceptable excipients are also naturally occurring such as blood that have the T cells. Thus, claim 48 also embraces compositions that are not markedly different from a naturally occurring T cell in blood.
(ii) Does the claim recite additional elements that integrate the judicial exception into a practical application? Claim 42 and 94 do not recite additional elements that integrate the judicial exception into a practical application because only the T cell with the arginine transporter is recited. Claim 44 and 96 do not recite additional elements that integrate the judicial exception into a practical application because only the T cell with the specifically listed arginine transporters are also naturally occurring are recited. Claims 95, 97-100 recite inherent features of the claimed cell and thus do not recite additional elements that integrate the judicial exception into a practical application.
Claim 48 recites an additional element of “pharmaceutically acceptable excipient” however, as noted above, it does not recite any specific excipient and embraces naturally occurring excipient such as blood that have the T cells. Furthermore, even in case, the generically recited “pharmaceutically acceptable excipient” is not naturally occurring, other consideration are relevant when evaluating whether the additional element integrates the exception into a practical application. MPEP 2106.04(d) presents the considerations that relevant to this analysis. In the instant case, the additional element of “pharmaceutically acceptable excipient” does not apply or use the judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition. Furthermore, the use of pharmaceutically acceptable excipient in pharmaceutical composition is routine such that the recited additional element is an insignificant extra-solution activity to the judicial exception. Thus, claim 48 does not recite an additional elements that integrate the judicial exception into a practical application.
2B) Significantly More
The claims 42, 44, 94-100 do not include additional elements that are sufficient to amount to significantly more than the judicial exception because claims 42, 44, 94-100 do not recite any additional element that could suggest that they could amount to an inventive concept.
Regarding claim 48, inclusion of the T cell in a generically recited pharmaceutically acceptable excipient was not found to integrate the judicial exception into a practical application. Furthermore, inclusion of additional elements that are well-understood, routine, conventional elements could not amount to an inventive concept that could provide significantly more to the judicial exception. Considering use of pharmaceutically acceptable excipient in making compositions is routine, claim 48 does not provide significantly more to the judicial exception.
Summary
On balance the relevant factors weigh against eligibility and claims 42, 44, 48, 94-100 do not qualify as eligible subject matter under 35 U.S.C. § 101.
Claim Rejections - 35 USC § 102- New, necessitated by claim amendments
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.
Rejection of Claim(s) 43 under 35 U.S.C. 102(a)(1) as being anticipated by London et al (WO 2018/138522 A1; 02 August 2018; IDS 8/15/2025) as evidenced by Fotiadis et al (Molecular Aspects of Medicine 34 (2013) 139–158) and Karunakaran et al (THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 286, NO. 36, pp. 31830–31838, September 9, 2011) is moot due to claim cancellation.
Rejection of Claim(s) 42 under 35 U.S.C. 102(a)(1) as being anticipated by London et al (WO 2018/138522 A1; 02 August 2018; IDS 8/15/2025) as evidenced by Fotiadis et al (Molecular Aspects of Medicine 34 (2013) 139–158) and Karunakaran et al (THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 286, NO. 36, pp. 31830–31838, September 9, 2011) is withdrawn to address newly added claim limitations.
Claim(s) 42, 88, 94-101 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by London et al (WO 2018/138522 A1; 02 August 2018; IDS 8/15/2025) as evidenced by Fotiadis et al (Molecular Aspects of Medicine 34 (2013) 139–158) and Karunakaran et al (THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 286, NO. 36, pp. 31830–31838, September 9, 2011).
Regarding claim 42 and 94, London discloses T cells expressing amino acid transporters such as SLC7A1, SLC7A2, SLC7A3, SLC7A4, SLC7A6, SLC7A9, SLC3A1, SLC3A2, SLC6A14; (page 3-4, bridging para; page 4, last para). See Table 1 and 2 in Fotiadis as evidence that CAT1 = SLC7A1, CAT2 = SLC7A2, CAT3 = SLC7A3, CAT4 = SLC7A4, y+LAT1 = SLC7A7, 4F2hc = SLC3A2, y+LAT2 = SLC7A6, b0,+AT = SLC7A9 and rBAT = SLC3A1 (=claimed a-g) and that these are capable of transporting arginine. See Abstract and Introduction-para 2 in Karunakaran as evidence that ATB0,+ = SLC6A14 (=claimed h) and this transports all essential amino acids, thus transports arginine.
London also discloses using vectors comprising nucleic acids encoding recombinant amino acid transporters recited above, the use of these vectors to transduce/transfect T cells and T cells transduced/transfected with such vectors (claims 14-17; claim 22; page 12, para 2).
Taken together, London discloses T cells genetically modified using vectors comprising nucleic acids encoding recombinant amino acid transporters recited above which are arginine transporters.
Regarding the priming of the genetically modified T-cells with a media comprising any amount of arginine for the purpose of increasing intracellular arginine levels to any extent and for any duration, recited in claim 42, a claim interpretation is provided for this indefinite limitation in the U.S.C. 112b rejection. T-cells genetically modified to express any one or more of the recited recombinant arginine transporters are inherently capable of increasing intracellular arginine at any level for any duration. London discloses the claimed genetically modified T-cells with each of the recited transporters. Thus, London’s cells have the same structure as the claimed cells and are inherently capable of increasing their intracellular arginine levels.
Regarding the property of the claimed genetically modified T-cells to survive in arginine-depleted environments, recited in claim 94, such as a tumor microenvironment, recited in claim 95, by increasing their intracellular arginine levels to a supraphysiological level such as 500-4000uM, as recited in claims 97-100, these property arise from the structure of the claimed cell and are inherent to the claimed cell. London discloses the claimed genetically modified T-cells with each of the recited transporters. Thus, London’s cells have the same structure as the claimed cells and are inherently capable of surviving arginine-depleted environments such as tumor-microenvironments by increasing their intracellular arginine levels to a supraphysiological level.
London discloses the elected species of CAT-2 in claims 42, 88 and 94 and 101.
Therefore, London anticipates the claimed invention.
Claim Rejections - 35 USC § 103- New, necessitated by claim amendments
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.
Rejection of Claim(s) 44 under 35 U.S.C. 103 as being unpatentable over London as applied to claim 42, 43 above, and further in view of NM_001008539.4 (May 7 2019; in PTO-892; Sequence alignment with SEQ ID NO: 184 in PTO-892), NM_001164771.2 (May 7 2019; IDS 8/15/2025), NM_001370337.1 (May 7 2019; IDS 8/15/2025), NM 001370338.1 (May 7 2019; IDS 8/15/2025), NM_003046.6 (May 7 2019; IDS 8/15/2025) or Bancel et al (US 2014/0010861 A1, Jan. 9, 2014) is withdrawn due to withdrawal of the rejection that the instant rejection relied upon.
Rejection of Claim(s) 48 under 35 U.S.C. 103 as being unpatentable over London as applied to claim 42 above, and further in view of Mussai et al (WO 2019/122936 A1, 27 June 2019; IDS 8/15/2025) is withdrawn due to withdrawal of the rejection that the instant rejection relied upon.
Claim(s) 44, 89, 90, 96, 102, 103 is/are rejected under 35 U.S.C. 103 as being unpatentable over London as applied to claim 42, 94 above, and further in view of NM_001008539.4 (May 7 2019; ref of record), NM_001164771.2 (May 7 2019; IDS 8/15/2025), NM_001370337.1 (May 7 2019; IDS 8/15/2025), NM_003046.6 (May 7 2019; IDS 8/15/2025) or NP_003037.4 (Sep 8, 2009; Sequence and alignment with SEQ 194 in PTO-892).
Regarding claim 44, 90, 96, 103, London teaches the T cell of claims 42 and 94 that expresses the CAT-2 (=SLC7A2; see analysis in U.S.C 102 rejection above; page 3-4, bridging para; page 4, last para; claims 14-17; claim 22; page 12, para 2). London also teaches the use of vectors comprising nucleic acids that encode recombinant amino acid transporters such as CAT-2 to transduce/transfect T cells to generate T cells expressing recombinant amino acid transporters such as CAT-2 (claims 14-17; claim 22; page 12, para 2).
London does not teach the exact sequence of CAT-2 gene, mRNA, protein coding sequence (CDS) or protein. However, these sequences were known in the art.
NM_001008539.4 is the mRNA sequence of CAT-2 which is identical to SEQ ID NO: 184, required for claims 44 and 96 (See Sequence alignment with SEQ ID NO: 184 provided in prior PTO-892).
NM_001164771.2 is the mRNA sequence of CAT-2 which is identical to SEQ ID NO:185, required for claims 44 and 96.
NM_001370337.1 is the mRNA sequence of CAT-2 which is identical to SEQ ID NO:186, required for claims 44 and 96.
NM_003046.6 is the mRNA sequence of CAT-2 which is identical to SEQ ID NO:188 and comprises the CDS sequence identical SEQ ID NO: 196 that encodes the protein sequence of NP_003037.4 which is identical to SEQ ID NO: 194 (See Sequence alignment with SEQ ID NO: 194 provided in PTO-892), required for claims 44, 89, 90, 96, 102, 103.
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the known sequences for CAT-2 as taught by any one of NM_001008539.4, NM_001164771.2, NM_001370337.1, or, NM_003046.6 that comprises CDS that encodes NP_003037.4 in the nucleic acids of London that encode CAT-2. An ordinary artisan would be motivated to use the sequences taught by any one of NM_001008539.4, NM_001164771.2, NM_001370337.1, or, NM_003046.6 because London does not teach the exact sequence. An ordinary artisan would reasonably expect to generate a T cell expressing CAT-2 using the sequences taught by any one of NM_001008539.4, NM_001164771.2, NM_001370337.1, NM_003046.6 because London teaches methods to generate vectors using sequences that encode amino acid transporters and methods to use such vectors to generate T cells (Example 1-4).
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in
the art at the effective time of filing of the invention, especially in the absence of evidence to the
contrary.
Claim(s) 48 is/are rejected under 35 U.S.C. 103 as being unpatentable over London as applied to claim 42 above, and further in view of Mussai et al (WO 2019/122936 A1, 27 June 2019; IDS 8/15/2025).
London teaches the T cell of claims 42 that expresses an arginine transporter; for example, SLC7A2 (see analysis in U.S.C 102 rejection above; page 3-4, bridging para; page 4, last para; claims 14-17; claim 22; page 12, para 2).
Regarding claim 48, London teaches pharmaceutical composition comprising the T cell and contemplates their use in treating cancer (page 13, para 3; claims 19-20). London does not explicitly teach that the pharmaceutical composition comprising the T cell also comprises a pharmaceutically acceptable excipient. However, use of excipients in pharmaceutical compositions, including pharmaceutical compositions comprising T cells, is common and routine in the art.
Mussai is also directed at use of T cells for cancer treatment (page 9, para 1-5) and teaches use of pharmaceutically acceptable carriers such as excipients in pharmaceutical compositions comprising T cells (page 44, para 3 and 5). Mussai teaches that “A pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject.” (page 44, para 5). Mussai teaches various excipients such as sterile water, physiological saline, glucose, dextrose, or the like which are selected depending upon the route of administration and the preparation desired (page 47, para 1). Mussai notes that “Standard texts may in some aspects be consulted to prepare suitable preparations.” (page 47, para 1).
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to include pharmaceutically acceptable excipients taught by Mussai in the pharmaceutical composition of London that also comprises T cells. An ordinary artisan recognizes the routine use of excipients in manufacture of pharmaceutical compositions, such as also noted by Mussai. An ordinary artisan would be motivated to include an excipient in London’s pharmaceutical compositions to generate a desired preparation of the pharmaceutical composition, such as also taught by Mussai, and such an inclusion would not require inventive ingenuity. Considering that excipients in pharmaceutical compositions are not the active therapeutic and Mussai teaches several excipients, an ordinary artisan reasonably expects to include a pharmaceutically acceptable excipient in London’s pharmaceutical composition.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claim(s) 91-92, 104-105 is/are rejected under 35 U.S.C. 103 as being unpatentable over London as applied to claim 42, 94 above, and further in view of Habermeier et al (Two Amino Acid Residues Determine the Low Substrate Affinity of Human Cationic Amino Acid Transporter-2A*. JBC, Vol. 278, No. 21, 2003).
Regarding claim 91-93, 104-106, London teaches the T cell of claims 42 and 94 that expresses the CAT-2 (=SLC7A2; see analysis in U.S.C 102 rejection above; page 3-4, bridging para; page 4, last para; claims 14-17; claim 22; page 12, para 2). London also teaches the use of vectors comprising nucleic acids that encode recombinant amino acid transporters such as CAT-2 to transduce/transfect T cells to generate T cells expressing recombinant amino acid transporters such as CAT-2 (claims 14-17; claim 22; page 12, para 2).
London does not teach the use of the specifically recited CAT-2A isoforms that comprise a R369E and/or N381i mutations, recited in claims 91 and 104, with a sequence of SEQ ID NO: 198-200, recited in claims 92 and 105, encoded by a sequence of SEQ ID NO: 201-203, recited in claims 93 and 106.
Habermeier teaches CAT-2A isoforms that comprise a R369E and/or N381i mutations (as required by claims 91 and 104; Figure 1C). Habermeier teaches the proteins sequence of CAT-2A isoforms that comprise a R369E and/or N381i mutations. Figure 1A shows the sequence of CAT2A WT and location of mutations in transmembrane domain VIII resulting in sequence identical to SEQ ID NO: 200 that comprises both mutations (as required by claims 92 and 105; See sequence alignment in PTO-892).
Regarding the CAT-2A isoforms that comprise a R369E and/or N381i mutations, Habermeier teaches that these mutations reduce the Km of CAT-2A for arginine i.e. allow for arginine binding and transport at lower arginine levels (Fig 2, 3).
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the T-cell of London to express CAT-2A isoforms that comprise a R369E and/or N381i mutations, as taught by Habermeier. An ordinary artisan would be motivated to modify London’s T-cells to express CAT-2A isoforms that comprise a R369E and/or N381i mutations because it would all the T-cells to bind and transport arginine at lower concentrations. An ordinary artisan could reasonably modify London’s T-cells to express CAT-2A isoforms that comprise a R369E and/or N381i mutations because London teaches the general methods to generate vectors using sequences that encode amino acid transporters and methods to use such vectors to generate T cells (Example 1-4) and Habermeier teaches methods to generate CAT2A cDNA with mutations that result in the mutated proteins (Site-directed Mutagenesis and Generation of Chimeric cDNAs).
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Allowable Subject Matter
SEQ ID NO: 201-203 are nucleotide sequences that encode the CAT-2A isoforms that comprise a R369E and/or N381i mutations. These sequences appear to be codon optimized and are not known in the prior art.
Response to Arguments
Applicant's arguments filed 3/31/2026 regarding the Improper Markush Rejection have been fully considered but they are not persuasive.
Applicant argue that “the arginine transporters recited in the Markush groupings of
claims 42 and 44 (and of new claims 94 and 96) are art-recognized classes of solute carrier
proteins that transport arginine, enabling cellular arginine uptake. “(page 8, last para). Applicant also allege that “specification provides functional characterization for each arginine transporter in the Markush grouping, including apparent KM values (affinity for arginine), sodium dependence, and transstimulation properties for CAT-1, CAT-2, CAT-3, CAT-4, y+LAT1/4F2hc, y+LAT2/4F2hc, b0,+AT/rBAT, and ATB0,+. This data demonstrates that all members of the Markush groupings share the functional property of arginine transport, which is the property mainly responsible for their function in the instant claims (i.e., to increase the intracellular arginine level in the genetically modified T-cell or to allow the T-cell to survive in an arginine-depleted environment)” (page 9, para 1).
This is not persuasive because, as the Applicant also notes that an art-recognized class requires that “there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention” (page 7, last para). As the analysis shows in the Improper Markush Rejection the art recognizes these transporters to be structurally and functionally distinct. Fotiadis identifies the different groupings of the claimed amino acid transporter, each of which is not categorized as a cationic amino acid transporter, let alone an arginine transporter. Applicant fail to indicate where in the specification demonstrates that the Markush groupings share the functional property of arginine transport in the context of the claimed invention. Apparent Km values listed in Table 1 do not indicate how these “apparent” Km values were calculated and if these Km values are for arginine. The specification describes Table 1 as “human amino acid transporters capable of bidirectional transport of cationic amino acids such as arginine” (emphasis added; page 81). The specification does not identify which of the listed transporter allow for unidirectional transport of arginine or allow for increase in intracellular arginine. Furthermore, no Km is listed for CAT-4. This is in agreement with the art also, since CAT-4 does not transport any amino acid. Thus, although CAT-1,2,3 may be a proper Markush, other transporters claimed do not belong to an art-recognized class or have single structural similarity.
Applicant's arguments filed 3/31/2026 regarding the U.S.C. 101 rejection have been fully considered but they are not persuasive.
Applicant argue that “a T-cell having an exogenous recombinant arginine transporter by
definition cannot be considered to be indistinct from a naturally occurring counterpart. Furthermore, the T-cell has an increased level of intracellular arginine from being primed in an
arginine media, and also for this reason is distinct from a naturally occurring counterpart.” (page 9, para 5). Regarding new claims, also instantly rejected under U.S.C. 101, Applicant argue “Like claim 42, claim 94 is directed to a T-cell that, by virtue of having an
exogenous recombinant arginine transporter, is distinct from any naturally occurring T-cell
counterpart. Furthermore, the limitation that the T-cell comprises an intracellular arginine level
that allows the T-cell to survive in an arginine-depleted environment reflects a specific cellular
state achieved through the genetic modification, one not characteristic of unmodified T-cells,
and thus provides an additional basis on which claim 94 is distinct from any naturally occurring
counterpart.”
In response, as detailed in the rejection above, recitation of terms such as “recombinant” or “exogenous” does not result in the claimed cells being markedly different in characteristics from their naturally-occurring counterparts. Indeed the claimed cells are not product of nature but a nature-based product. “It is important to keep in mind that product of nature exceptions include both naturally occurring products and non-naturally occurring products that lack markedly different characteristics from any naturally occurring counterpart.” (MPP 2106.04(b)(II). The claimed cell have a structural characteristic of a T-cell that expresses one or more of the recited transporters. These transporters, exogenous or endogenous, once expressed in the cell, are indistinct. Exogenous expression of transporters may result in overexpression of the transporter however this is not a requirement. Furthermore, naturally occurring T-cells increase expression of arginine transporters, at least CAT-1 and CAT-3 i.e. naturally occurring T-cells also overexpress arginine transporters. Thus, even overexpression of a transporter cannot lend a markedly different characteristic to the claimed cell. Regarding the allegation regarding unmodified T-cells being unable to survive in arginine depleted environment, Applicant’s data in Fig 3C and 4 shows that unmodified T-cells indeed survive in arginine-depleted environments. See Control showing %change in cell number is not -100% i.e. at least some cells are surviving. Furthermore, Werner showed that once stimulated, T-cells overexpress certain arginine transporters such that they are capable of arginine uptake even in arginine depleted environments (Figure 1) allowing them to not only survive but proliferate in such environments (Figure 6). Thus, the inherent feature of increased intracellular arginine levels or ability to survive arginine-depleted environments, as recited in the claims, are also present in naturally-occurring T-cells.
Applicant’s arguments with respect to the U.S.C. 102 rejection of claim(s) 42 have been considered but are moot because the new ground of rejection necessitated by claim amendments.
Arguments pertinent to the instant U.S.C. 102 rejection of claim(s) 42 are addressed below.
Applicant argue that London does not disclose the newly added claim limitation directed to priming the genetically modified T-cells in a media comprising arginine to increase the intracellular arginine levels (page 10, para 5). Similarly, Applicant argue that London does not disclose the newly added claim 94 that recites that the cells have an intracellular arginine levels that allow the T-cell to survive in an arginine-depleted microenvironment (page 10, last para). Applicant allege that “London discloses T-cells that are modified to function in tryptophan-limited
environments, wherein the T-cells express glutamine and tryptophan transporters to overcome
tryptophan depletion. London's focus and working examples are entirely focused on glutamine/tryptophan transport, not arginine transport.” (page 11, para 1).
In response, contrary to Applicant’s allegation London’s disclosure is not limited to “T-cells that are modified to function in tryptophan-limited environments”. London specifically discloses T-cells expressing the claimed transporters (pages 4, 5). The newly added limitation to claim 42 does not alter the structure of the claimed T-cell, see claim interpretation provided in U.S.C. 112b rejection above. Similarly for new claim 94. These limitations only recite a feature of the cell and this feature must arise from the structure of the cell i.e. is inherent to the cell.
Of note, the specification does not measure intracellular arginine levels in any genetically-modified T-cell for any duration, let alone all the various genetically-modified T-cells embraced by the claims (any combination of a-h). Thus there is no guidance if the claimed genetically modified T-cells with any of the recited transporters have increased arginine levels after being primed in a media that comprises any amount of arginine and if so, to what level and for how long after priming is this alleged increase maintained. Furthermore, there is no evidence that priming is even required for the genetically modified T-cells to increase their arginine levels, including their ability to increase arginine levels in arginine-depleted environments. On the contrary, Werner teaches that priming is not required and increase in arginine-transporter expression is the only requirement for T-cells to survive arginine-depleted environments (compare Fig 1A i.e. primed T-cells with Fig 1B unprimed T-cells; Fig 3 that shows increase in CAT-1 even in arginine-depleted environment).
Applicant’s arguments with respect to the U.S.C. 103 rejection of claim(s) 44 have been considered but are moot because the new ground of rejection necessitated by claim amendments.
Arguments pertinent to the instant U.S.C. 103 rejection of claim(s) 44 are addressed below.
Applicant argue that “London does not teach genetically modified T-cells primed in a media comprising arginine, thereby to increase the intracellular arginine level in the genetically modified T-cell. None of the GenBank sequences or Bancel make up for this deficiency.” (page 12, para 1).
In response, as discussed above in the response to arguments pertaining to U.S.C. 102 rejection of claims over London, London discloses T-cells with the claimed structure that inherently comprise the claimed feature. Since London does not suffer from the alleged deficiency, GenBank sequences or Bancel are not required to supplement it.
Applicant’s arguments with respect to the U.S.C. 103 rejection of claim(s) 48 have been considered but are moot because the new ground of rejection necessitated by claim amendments.
Arguments pertinent to the instant U.S.C. 103 rejection of claim(s) 48 are addressed below.
Applicant argue that “London fails to teach or suggest priming T-cells in a media comprising arginine, thereby to increase the intracellular arginine level in the genetically modified T-cell. Mussai fails to remedy the defect..” (page 12, para 7).
In response, as discussed above in the response to arguments pertaining to U.S.C. 102 rejection of claims over London, London discloses T-cells with the claimed structure that inherently comprise the claimed feature. Since London does not suffer from the alleged deficiency, Mussai is not required to supplement it.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MATASHA DHAR whose telephone number is (571)272-1680. The examiner can normally be reached M-F 8am-4pm (EST).
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/MATASHA DHAR/Examiner, Art Unit 1632
/EMILY A CORDAS/Primary Examiner, Art Unit 1632
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