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 .
Applicant's amendments to the claims filed on 07-03-2024 have been received and entered. Claims 1-25 have been canceled. Claims 26-61 have been added. Claims 26-61 are pending in the instant application.
Election/Restrictions
Applicant’s election without traverse of Group 1(claims 26-34, 43-51, 60 and 61) in the reply filed on 07-27-2026 is acknowledged.
Claims 35-42 and 52-59 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07-27-2026.
Applicant elects the following species without traverse: For claim 27, species (2) is elected; for claim 28, species (4) is elected; for claim 30, species (2) is elected; for claim 31, species (2) is elected; for claim 32, species (6) is elected; for claim 33, species (2) is elected; for claim 44, species (2) is elected; for claim 45, species (4) is elected; for claim 47, species (2) is elected; for claim 48, species (2) is elected; for claim 49, species (2) is elected; and for claim 50, species (2) is elected. Upon further consideration, election of species requirement is hereby withdrawn, and all the non-elected species are hereby rejoined with the elected invention.
Claims 26-34, 43-51, 60 and 61 are under consideration.
Priority
This application is a CON of PCT/CN2022/143567 filed on 12/29/2022 that claims priority from foreign application no CHINA 202210005890.X filed on 01/05/2022.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 07-03-2024 and 02-10-2026 are in compliance with the provisions of 37 CPR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Claim Objections
Claim 46 is objected to because of the following informalities:
claim 46 is objected to because it comprises a comma adjacent to the period at the end of the claim that is somewhat confusing. This appears to be a typographical error in that the limitation recited prior to the comma appears to be complete (see below).
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Appropriate correction is required.
Claim Rejections - 35 USC § 101
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.
Claims 26-34 and 43-51 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature and abstract idea without significantly more.
Step 1: Is the claim to a process, machine, manufacture or composition of matter?
Independent claims 26 and 43 both recite “ An isolated T cell receptor or a fragment thereof”. Here, because “an isolated T cell receptor or a fragment thereof” is a composition of matter, the claim is to at least one statutory category of invention (Step 1: YES).
Step 2(A), Prong 1: Does the claim recite an abstract idea, law of nature or natural phenomenon?
Under the broadest reasonable interpretation, the terms of the claim are presumed to have their plain meaning consistent with the specification as it would be interpreted by one of ordinary skill in the art. See MPEP 2111.
Independent claims 26 recite “An isolated T cell receptor or a fragment thereof, the T cell receptor comprises a TCR α chain and a TCR β chain, wherein the TCR β chain comprises a TCR β chain variable region and a TCR β chain constant region, the TCR β chain constant region comprises a TCR β chain extracellular constant region, a TCR β chain transmembrane region, and a TCR β chain intracellular constant region that are connected in a sequential order, and the TCR β chain intracellular constant region is selected from: (1) a mutated TCR β chain intracellular constant region, wherein the mutated TCR β chain intracellular constant region is a wild-type TCR β chain intracellular constant region with at least one lysine mutated to arginine or alanine; or (2) a mutated TCR β chain intracellular constant region comprising an amino acid sequence set forth in SEQ ID NO: 10 or consisting of the amino acid sequence.
Independent claims 43 recite “An isolated T cell receptor or a fragment thereof, the T cell receptor comprises a TCR α chain and a TCR β chain, wherein the TCR α chain comprises a TCR α chain variable region and a TCR α chain constant region, the TCR α chain constant region comprises a TCR α chain extracellular constant region, a TCR α chain transmembrane region, and a TCR a chain intracellular constant region that are connected in a sequential order, and the TCR α chain intracellular constant region is selected from: (1) a mutated TCR α chain intracellular constant region, wherein the mutated TCR α chain intracellular constant region is a wild-type TCR α chain intracellular constant region with at least one serine mutated to alanine; or (2) a mutated TCR α chain intracellular constant region comprising an amino acid sequence set forth in SEQ ID NO: 4 or consisting of the amino acid sequence.”
The markedly different characteristics analysis is performed by comparing the nature-based product limitation in the claim to its naturally occurring counterpart to determine if it has markedly different characteristics from the counterpart. MPEP 2106.04(c) (11). In the instant case:
According to the specification of the claimed invention: “The present disclosure provides a TCR α chain or fragment thereof isolated from a T cell receptor (TCR)” (see the specification [0015], page 3), “The term "isolated" refers to materials that have been removed from their natural state or artificially manipulated in other ways, such as a chains, β chains, T cell receptors, and nucleic acids as described in this article…. The isolated material can be in the form of natural chemically synthesized, or recombinant. The isolated materials can also be or alternatively be in the form of enriched, partially purified, or purified.” (see the specification [0215], page 26). Because claims 26 and 43 recite the term “fragment thereof” in the context of the claimed T cell receptor as a whole, the claims encompass an isolated fragment of T cell receptor ( e.g., a fragment of a natural occurring TCR α chain and/or a TCR β chain, or an isolated TCR α chain or an isolated TCR β chain itself) that has been isolated from their natural state.
Both Items (2) of claim 26 and claim 43 recites “comprising an amino acid sequence set forth in SEQ ID NO: 10” and “comprising an amino acid sequence set forth in SEQ ID NO: 4”, respectively. It is noted that recitation of “A” and “The” can result in very different scope. In the instant case, the recitation of “an” in claim 26 (and claim 43) encompasses amino acid sequences that comprise the full-length sequence of SEQ ID NO: 10 (or SEQ ID NO: 4) or any portion of SEQ ID NO: 10 (or SEQ ID NO: 4). In other words, the use of the word “an” in this context means that these claims can be interpreted as encompassing embodiments where a recited polypeptide (e.g., a TCR β chain or TCR α chain) comprises as little as a two amino acid length sequence in common with the sequence described by the recited sequence identifier (e.g., SEQ ID NO: 10; etc.). The recitation of “the” would claim only amino acid sequences that comprise the full length of SEQ ID NO: 10 (or SEQ ID NO: 4), with or without additional amino acids at either or both ends. Thus, with the claims as currently written, the isolated T cell receptor can encompass any natural portion of SEQ ID NO: 10 and SEQ ID NO: 4 and the term “an” may not exclude the natural origin.
Step 2(A), Prong 2: Do the claims recite additional elements that integrate the judicial exception into a practical application?
In view of foregoing analysis, it is apparent that the claims recite judicial exceptions that are
product of nature. While the claims would still be patent-eligible if “the claims as a whole integrate the recited judicial exceptions (product of nature) into a practical application of the exception”. The additional limitations recited in the instant claims do not integrate the judicial exceptions into a practical application of the recited judicial exceptions. For example, claim 26 is directed to an isolated T cell receptor or a fragment thereof, the T cell receptor comprises a TCR α chain and a TCR β chain, wherein the TCR β chain comprises a TCR β chain variable region and a TCR β chain constant region, the TCR β chain constant region comprises a TCR β chain extracellular constant region, a TCR β chain transmembrane region, and a TCR β chain intracellular constant region that are connected in a sequential order. Claim 43 is directed to an isolated T cell receptor or a fragment thereof, the T cell receptor comprises a TCR α chain and a TCR β chain, wherein the TCR α chain comprises a TCR α chain variable region and a TCR α chain constant region, the TCR α chain constant region comprises a TCR α chain extracellular constant region, a TCR α chain transmembrane region, and a TCR a chain intracellular constant region that are connected in a sequential order. Claims 27-34 and 44-51 do not integrate the judicial exception of product of nature into a practical application of the judicial exception.
In summary, there are no additional elements recited in the claims, considered individually or in
combination, that integrate the judicial exception of product of nature into a practical application of the judicial exception and the claims are therefore considered to be directed to the judicial exceptions recited in claims 1 (Step 2A, Prong II: NO).
Step 2(B): Does the claim recite additional elements that amount to significantly more than the
judicial exception?
Claims 27-34 and 44-51 do not add an inventive concept beyond routine, conventional, or well-understood activities. Thus, the claims recite a naturally occurring T cell receptor/polypeptide fragments that do not differ markedly, if at all, from naturally occurring T cell receptor/polypeptide fragments. Therefore, the answer to step 2B of the 101 Subject Matter Eligibility Test is “No” (Step 2B: NO).
Conclusion: Given the analysis above, it is reasonable to conclude that claims 27-34 and 44-51 encompass embodiments that are not directed to patent-eligible subject matter.
Claim Rejections - 35 USC § 112
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 27, 28, 32, 44, 45, 49, 61 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 27, 28, 32, 44, 45, 49, 61 is vague and indefinite because they recite the phrase “derived from” and the metes and bounds of how T cell receptor can be “derived from” human, mouse,
or other mammalian species are not clear. Without a clear statement of the process by which the TCR α or β chain is derivatized, it is not possible to know the metes and bounds of a “derivative” because any given starting material can have many different derivatives depending on the process of derivatization. In other words, it is not clear just how much a given protein sequence can be changed from the human, mouse or other mammalian sequence and still be considered as being a ‘derivative’ of that human, mouse or other mammalian sequence. This rejection could be overcome by substituting “isolated” for “derived” in the claims.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 26 and 43 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Koning et al (Eur. J. Immunol. 1990. 20: 299-305)
Claims interpretation:
Because claims 26 and 43 recite the term “fragment thereof” in the context of the claimed T cell receptor as a whole, the claims encompass an isolated fragment of T cell receptor ( e.g., a fragment of a natural occurring TCR α chain and/or a TCR β chain, or an isolated TCR α chain or an isolated TCR β chain itself) that has been isolated from their natural state. Claim 26 read on any isolated alpha chain from any source because the alpha chain is a fragment of the claimed T-cell receptor and not restricted in any other way in claim 26. Likewise, the ‘fragment’ language of claim 43 makes it encompass embodiments where any beta chain has been isolated. The term ‘isolated’ in this instance could reasonably be interpreted as encompassing instances where the alpha and beta chains have been separated from one another and their normal cellular environment (e.g., sds-page gels; chromatography, etc.). Therefore, claims 26 and 43 encompass wildtype alpha chains and beta chains, respectively.
Regarding claims 26 and 43, Koning et al teach the T cell receptor (TcR)α/β-CD3 complex and Figure 1: an immunoprecipitation experiment with SDS-PAGE showing the isolated alpha and beta chains on the SDS-PAGE gel:
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Thus, claims 26 and 43 are anticipated by Koning et al.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 26-29, 32 , 33 and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Juneja et al (Pub. No .: US 2021/0340215 A1, Pub. Date : Nov. 4, 2021) in view of Wang et al (Pub. No .: US 2022/0280566 A1, Foreign Application Priority Data Apr. 16 , 2019).
Regarding to claim 26, Juneja et al teach “The present disclosure provides T cell receptors (TCRs) against peptide -MHC complexes, isolated nucleic acid molecules encoding TCRs against peptide -MHC complexes” (abstract) and “T cell receptors ( TCRs) are members of the immunoglobulin superfamily and usually consist of two subunits, namely the α- and β-subunits. These possess one N -terminal immunoglobulin ( Ig )-variable (V) domain, one Ig -constant (C) domain, a transmembrane/cell membrane -spanning region, and a short cytoplasmic tail at the C-terminal end.” ([0002], page 1). Juneja et al teach “FIG . 3A represents a graphical diagram of an exemplary vector design, incorporating a TCR alpha chain and a TCR beta chain construct; wherein the TCR alpha- and beta -chain constructs comprise nucleic acid sequences encoding a variable (V) , a diversity (D) , only in beta chain construct) a joining (J) and a constant (C) region for each of a TCR alpha (α) chain and a TCR beta (β) chain as shown in the diagram” ([0400], page 48).
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Juneja et al teach The TCRs provided herein target may be engineered TCRs , for example, chimeric antigen receptors (CARS). CARS can be composed of three regions: an ectodomain, a transmembrane domain and an endodomain ([0171], page 23). Juneja et al teach “An ectodomain can be the region of the receptor that is exposed to the extracellular fluid and can consist of an antigen recognition region ” ([0172], page 23). Juneja et al teach “A transmembrane domain can be a hydrophobic domain that spans the membrane” ([0173], page 23). Juneja et al teach “an endodomain can be a functional intracellular portion of a receptor, such as a TCR or CAR” ([0174], page 23).
Juneja et al do not teach “mutated TCR β chain intracellular constant region, wherein the mutated TCR β chain intracellular constant region is a wild-type TCR β chain intracellular constant region with at least one lysine mutated to arginine or alanine”. Wang et al cure the deficiency.
Wang et al teach “The present invention provides a method for optimization and modification of CAR-T, in which all lysine sites in an intracellular segment of CAR are mutated into arginine, thereby blocking ubiquitination modification of the CAR after antigen challenge. This strategy is applicable to different CARs and changing different intracellular costimulatory domains , and in particular provides a solution to the problem of poor proliferation of CAR-T in solid tumors” (Abstract). Wang et al teach “The present invention mutates all lysine sites in an intracellular segment of the CAR into arginine, thereby blocking the ubiquitination modification of the CAR after antigen challenge. This strategy is applicable to different CARs and changing different intracellular costimulatory domains” ([0024], page 1-2).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the engineered TCRs such as chimeric antigen receptors (CARS) ([0171], page 23) as taught by Juneja et al by mutating all lysine sites in an intracellular segment of the CAR into arginine, thereby blocking the ubiquitination modification of the CAR as taught by Wang et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because
Wang et al teach “method for optimization and modification of CAR-T, in which all lysine sites in an intracellular segment of CAR are mutated into arginine, thereby blocking ubiquitination modification of the CAR after antigen challenge…. and in particular provides a solution to the problem of poor proliferation of CAR - T in solid tumors” (Abstract) and “Studies have demonstrated that enhancing the proliferative capacity of CAR-T cells in vivo can significantly improve the efficacy of CAR-T therapy, both in hematologic tumor therapy and solid tumor therapy, which provides a direction to optimize CAR-T design” ([0003], page 1). Specifically, Wang et al teach “The results of the downregulation and degradation of CAR-T under antigen challenge were shown in FIG . 1” ([0123], page 12) and “An obvious ubiquitin -modified band was formed 5 minutes after WT CAR interacted with the target cells , while KR-CAR could not be modified by ubiquitin before and after challenge , showing that mutation of the lysine site in the intracellular segment of CAR could effectively block the ubiquitin modification of CAR.” ([0124], page 12).
Wang et al teach “FIG . 2 is a graph showing results of down-regulation and degradation inhibited by KR -mutated CAR…. FIG . 2E shows the effect of KR mutation on degradation of CD19 41BBC CAR in human primary T cells. FIG. 2F is a quantitative result of FIG . 2E, and KR mutation effectively inhibits the degradation of CAR in this reaction” ([0030], page 2)
Wang et al teach “the modified CAR-T can more effectively infiltrate the tumor tissue for killing . Under the same T cell injection dose, the modified CAR-T can more effectively control the development of the tumor” ([0026], page 2)
Additionally, while Juneja et al identify CD3 -zeta intracellular domain as an exemplary intracellular/endodomain of a TCR/CAR ([0174], page 23), Wang et al teach CAR contains an intracellular domain comprising a costimulatory signaling region and a CD3-zeta intracellular region being mutated on lysine in that intracellular region to arginine ([0041]-[0047], page 3).
One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Wang et al were successful in mutating all lysine sites in an intracellular segment of CAR into arginine and effectively inhibiting the degradation of CAR.
Regarding to claim 27, Juneja et al teach:
“Among the provided TCRs are humanized and human TCRs…… A “human TCR ” is a TCR with an amino acid sequence corresponding to that of a TCR produced by a human or a human cell , or non -human source that utilizes human TCR repertoires or other human TCR -encoding sequences , including human TCR libraries …… Human TCRs may be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human TCRs or intact TCRs with human variable regions in response to antigenic challenge.” ([0134], page 16)
“the TCR comprises a beta chain having a sequence of SEQ ID NO : 364” (see page 7 - [0023] and table 2, page 66). The SEQ ID NO: 9 (MAMVKKKNS) of the claimed invention is 100% identical to SEQ ID NO : 364 of Juneja et al (see below).
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Regarding to claim 28, Juneja et al teach:
Juneja et al teach “The present disclosure provides T cell receptors (TCRs) against peptide -MHC complexes, isolated nucleic acid molecules encoding TCRs against peptide -MHC complexes” (abstract) and “T cell receptors ( TCRs) are members of the immunoglobulin superfamily and usually consist of two subunits, namely the α- and β-subunits. These possess one N -terminal immunoglobulin ( Ig )-variable (V) domain, one Ig -constant (C) domain, a transmembrane/cell membrane -spanning region, and a short cytoplasmic tail at the C-terminal end.” ([0002], page 1). Juneja et al teach “FIG . 3A represents a graphical diagram of an exemplary vector design, incorporating a TCR alpha chain and a TCR beta chain construct; wherein the TCR alpha- and beta -chain constructs comprise nucleic acid sequences encoding a variable (V) , a diversity (D) , only in beta chain construct) a joining (J) and a constant (C) region for each of a TCR alpha (α) chain and a TCR beta (β) chain as shown in the diagram” ([0400], page 48).
“Among the provided TCRs are humanized and human TCRs…… A “human TCR ” is a TCR with an amino acid sequence corresponding to that of a TCR produced by a human or a human cell , or non -human source that utilizes human TCR repertoires or other human TCR -encoding sequences , including human TCR libraries …… Human TCRs may be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human TCRs or intact TCRs with human variable regions in response to antigenic challenge.” ([0134], page 16) (For claim 28 item (1) and wherein the TCR a chain further comprises a TCR a chain variable region.).
Regarding to claim 29, Wang et al teach “the antigen recognition region is selected from a single chain antibody against a tumor surface antigen , and the tumor surface antigen is selected from one or more of CD19 , CD123 , CD30 , BCMA, Her2, IL13Ra2 and GD2 ”.
Regarding to claim 32, Juneja et al teach: “TCR alpha chain construct comprises a variable region having at least 80% sequence identity to or 100% sequence identity to SEQ ID NO: 568” ([0722], page 88 and table 2-page 73- see below). The SEQ ID NO: 1 (MAMVKKKNS) of the claimed invention is 100% identical to SEQ ID NO : 568 of Juneja et al (see below).
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Regarding to claim 33, Juneja et al teach SEQ ID NO : 363 and SEQ ID NO : 380 which are 100% and 99.3% identical to SEQ ID NO: 5 and SEQ ID NO: 12 of the claimed invention.
Juneja et al teach “In some embodiments, the TCR comprises an alpha chain having a sequence of SEQ ID NO: 363” ([0023], page 7 and table 2 page 66). The SEQ ID NO: 5 of the claimed invention is 100% identical to SEQ ID NO : 363 of Juneja et al (see below).
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Juneja et al teach “the TCR comprises a beta chain having a sequence of SEQ ID NO: 380” ([0023], page 7 and table 2 page 67). The SEQ ID NO: 12 of the claimed invention is 99.3% identical to SEQ ID NO : 363 of Juneja et al (see below).
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Regarding to claim 34,
Wang et al teach “the extracellular domain further includes a signal peptide and or a hinge region to form a signal peptide- antigen recognition region and hinge region connected in sequence” ([0055], page 3), and “Preferably, the signal peptide is selected from a CD8α signal peptide and or the hinge region is selected from a CD8α hinge region .” ([0056], page 3)
Juneja et al also teach “An ectodomain can be the region of the receptor that is exposed to the extracellular fluid and can consist of an antigen recognition region …. In some embodiments, an ectodomain further comprises and a signal peptide. A signal peptide can direct the nascent protein into the endoplasmic reticulum.” ([0172], page 23).
Claims 30-31 are rejected under 35 U.S.C. 103 as being unpatentable over Juneja et al (Pub. No .: US 2021/0340215 A1, Pub. Date : Nov. 4, 2021) in view of Wang et al (Pub. No .: US 2022/0280566 A1, Foreign Application Priority Data Apr. 16 , 2019) as applied to claims 26-29, 32 and 34 above, and further in view of Morgan et al (Pub. No.: US 2009/0304657 A1, Pub. Date: Dec. 10, 2009).
The teachings of Juneja et al and Wang et al above are incorporated herein in their entirety.
Juneja et al and Wang et al do not teach amino acid sequence set forth in the SEQ ID No in Claims 30-31. Morgan et al cure the deficiency.
Regarding to claim 30, Morgan et al teach “The invention provides a chimeric T cell receptor (TCR) comprising a variable region of a human TCR and a constant region comprising at least an extracellular domain of a constant region of a non-human TCR, as well as functional variants thereof.” (Abstract). Morgan et al teach “the β chain of the inventive TCR comprises the variable region of a β chain as set forth above. In this regard, the inventive chimeric TCR can comprise the amino acid sequence of any of SEQID NOs: 16, 17, 19, 20, 22, 23, 25, and 26” ([0040], page 4). The SEQ ID NO: 17 of the claimed invention is 100% identical to SEQ ID NO : 19 and 20 of Morgan et al (see below for Seq ID No: 19).
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Regarding to claim 31, Morgan et al teach “the variable region of the α chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 7, 9, 11, and 13,” ([0039], Page 4). The SEQ ID NO: 13 of the claimed invention is 100% identical to SEQ ID NO : 9 of Morgan et al (see below).
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Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of the above references by using amino acid sequence set forth in the SEQ ID No as taught by Morgan et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Morgan et al teach “The invention provides chimeric TCRs which have enhanced biological properties providing greater T cell responses against the antigen recognized by the chimeric TCR” ([0007], page 1) and “The invention provides chimeric T cell receptors (TCRs) which exhibit enhanced biological activity. For example, the inventive chimeric TCRs are marked by their higher capacity for cell Surface expression, stronger association with CD3, increased ability to secrete cytokines (e.g., IFNY, GM-CSF, and IL-2) upon antigen stimulation, and enhanced ability to recognize and kill tumor cells” ([0030], page 3), and “A method of improving the biological activity of a human TCR is further provided by the invention. The method comprises replacing the constant region of the human TCR with a constant region comprising at least an extracellular domain of a constant region of a non-human TCR” ([0013], page 1) and “provided are pharmaceutical compositions related to the inventive TCRs and methods of preventing or treating a disease, e.g., an infectious disease, cancer, in a host, methods of detecting a diseased cell in a host, and methods of improving the biological activity of a TCR.” (Abstract). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Morgan et al were successful in generation of chimeric T cell receptors (TCRs) which exhibit enhanced biological activity with detailed instructions and working examples.
Claims 43-50 are rejected under 35 U.S.C. 103 as being unpatentable over Morgan et al (Pub. No.: US 2009/0304657 A1, Pub. Date: Dec. 10, 2009) in view of Ishikura et al (THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 285, NO. 31, pp. 23916–23924, July 30, 2010, DOI 10.1074/jbc.M110.127936).
Regarding to claim 43, Morgan et al teach “The invention provides a chimeric T cell receptor (TCR) comprising a variable region of a human TCR and a constant region comprising at least an extracellular domain of a constant region of a non-human TCR, as well as functional variants thereof.” (Abstract), and “In the instance that the extracellular domain is of a murine constant region, the constant region of the chimeric TCR can comprise the extracellular domain of a murine constant region in combination with other parts, e.g., a transmembrane domain and/or an intracellular domain, of a constant region of a murine TCR or of a non-murine TCR. For example, the constant region of the chimeric TCR can comprise an extracellular domain of a constant region of a murine TCR in combination with a transmembrane domain and an intracellular domain of a constant region of a human TCR” ([0038], page 3-4), and “Alternatively or additionally, the chimeric TCR can comprise an α chain of a TCR and a β chain of a TCR. Each of the α chain and β chain of the inventive chimeric TCR can independently comprise any amino acid sequence” ([0040], page 4)
Morgan et al teach “The alpha and beta chains of functional variant chimeric TCRs shown in Table 7 are constructed using over lapping PCR techniques. Briefly, a forward primer that matches the 5' of the variable region and a reverse primer that contains the mutation in the constant region are used. The amplified product of this reaction is then used in a second PCR reaction as part of the template DNAs with the same forward primer and a reverse primer at the 3' of the constant region. The full length TCR is then cloned and sequenced to verify the mutation” ([0187], page 18).
Although Morgan et al teach the alpha and beta chains of functional variant chimeric TCRs contains the mutation in the constant region, Morgan et al do not teach a mutated TCR α chain intracellular constant region, wherein the mutated TCR a chain intracellular constant region is a wild-type TCR a chain intracellular constant region with at least one serine mutated to alanine. Ishikura et al cure the deficiency.
Ishikura et al teach “serine residues in the cytosolic tail of the T-cell antigen receptor α-chain mediate ubiquitination and endoplasmic reticulum-associated degradation of the unassembled protein” (Title). Ishikura et al teach “The T-cell antigen receptor (TCR) α-chain (TCR α) is a type I integral membrane protein that becomes ubiquitinated and targeted to the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway when it fails to assemble into the heteromeric TCR complex. Remarkably, TCR α has a cytosolic tail of only five amino acid residues (i.e. RLWSS), none of which is the conventional ubiquitin acceptor, lysine. Herein we report that substitution of two conserved serine residues in the cytosolic tail of TCR α to alanine decreased ubiquitination, whereas placement of additional serine residues enhanced it. Moreover, replacement of the cytosolic serine residues by other ubiquitinatable residues (i.e. cysteine, threonine, or lysine) allowed ubiquitination to take place. Serine-dependent ubiquitination perfectly correlated with targeting of TCR α for ERAD. We also found that this ubiquitination was mediated by the ER-localized ubiquitin ligase, HRD1. These findings indicate that serine-dependent, HRD1-mediated ubiquitination targets TCR α to the ERAD pathway” (Abstract)
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior arts to modify the method of Morgan et al by mutating TCR α chain intracellular constant region (a cytosolic tail) with at least one serine mutated to alanine as taught by Ishikura et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Ishikura et al teach “FIGURE 1. Mutation of two serine residues in the cytosolic tail of TCRα inhibits its ubiquitination and degradation.” (page 23918, Figure 1) and “The results presented here show that TCRα ubiquitination and ERAD targeting are dependent on two serine residues, Ser- 267 and Ser-268, in the cytosolic tail of TCRα. Substitution of these serine residues to alanine decreased ubiquitination of TCRα (Fig. 1), whereas placement of additional serine residues enhanced it (Figs. 2 and 3). Moreover, substitution of the serine residues by other ubiquitinatable residues (i.e. cysteine, threonine, or lysine) allowed ubiquitination to take place (Fig. 4)” (see page 23921, Discussion, right column, 3rd para. ). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Ishikura et al were successful in mutating two serine residues in the cytosolic tail of TCRα that inhibits its ubiquitination and degradation.
Regarding to claim 44, Morgan et al teach “…the constant region of the chimeric TCR can comprise an extracellular domain, a transmembrane domain, and an intracellular domain of a constant region of a murine TCR. In this respect, the chimeric TCR can comprise a constant region comprising any of SEQ ID NOs: 4 to 6,…” ([0038]), page 4), and “Alternatively or additionally, the chimeric TCR can comprise an α chain of a TCR and a β chain of a TCR. Each of the α chain and β chain of the inventive chimeric TCR can independently comprise any amino acid sequence.” ([0040], page 4). The SEQ ID NO: 3 of the claimed invention is 100% identical to SEQ ID NO : 4 of Morgan et al (see below).
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Regarding to claim 45, Morgan et al teach “the chimeric TCR comprises a constant region comprising an amino acid sequence of at least the extracellular domain of a constant region of a murine TCR ….. extracellular domain of a murine constant region in combination with other parts, e.g., a transmembrane domain and/or an intracellular domain of a constant region of a murine TCR or of a non-murine TCR” ([0038], page 3), and “the chimeric TCR can comprise an α chain of a TCR and a β chain of a TCR….. Preferably, the β chain of the inventive TCR comprises the variable region of a β chain as set forth above.” ([0040], page 4)
Regarding to claim 46, Morgan et al teach “The chimeric TCRs of the invention can have antigenic specificity for any antigen….. the antigen is a cancer antigen” ([0033], page 3), and “In a more preferred embodiment, the cancer antigen is MART-1, gp-100, p53, or NY-ESO-1” ([0035], page 3).
Regarding to claim 47, Morgan et al teach “The invention provides a chimeric T cell receptor (TCR) comprising a variable region of a human TCR and a constant region comprising at least an extracellular domain of a constant region of a non-human TCR, as well as functional variants thereof.” (Abstract). Morgan et al teach “the β chain of the inventive TCR comprises the variable region of a β chain as set forth above. In this regard, the inventive chimeric TCR can comprise the amino acid sequence of any of SEQID NOs: 16, 17, 19, 20, 22, 23, 25, and 26” ([0040], page 4). The SEQ ID NO: 17 of the claimed invention is 100% identical to SEQ ID NO : 19 and 20 of Morgan et al (see below for SEQ ID NO : 19 ).
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Regarding to claim 48, Morgan et al teach “the variable region of the α chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 7, 9, 11, and 13,” ([0039], Page 4). The SEQ ID NO: 13 of the claimed invention is 100% identical to SEQ ID NO : 9 of Morgan et al (see below).
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Regarding to claim 49, Morgan et al teach “the chimeric TCR comprises a constant region comprising an amino acid sequence of at least the extracellular domain of a constant region of a murine TCR. In this regard, the chimeric TCR can comprise a constant region comprising any of SEQ ID NOs: 1 to 3, or a combination thereof” ([0038], page 3) “Alternatively or additionally, the chimeric TCR can comprise an α chain of a TCR and a β chain of a TCR. Each of the α chain and β chain of the inventive chimeric TCR can independently comprise any amino acid sequence.” ([0040], page 4). The SEQ ID NO: 1 of the claimed invention is 100% identical to SEQ ID NO : 1 of Morgan et al (see below).
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Regarding to claim 50, Morgan et al teach SEQ ID NO : 15 and SEQ ID NO : 6 which are 100% and 99.3% identical to SEQ ID NO: 5 and SEQ ID NO: 12 of the claimed invention:
Morgan et al teach “the chimeric TCR can comprise an α chain of a TCR and a β chain of a TCR…. In this regard, the inventive TCR can comprise the amino acid sequence of any of SEQID NOs: 15, 18, 21, and 24 (amino acid sequences of α chain)” ([0040], page 4). The SEQ ID NO: 5 of the claimed invention is 100% identical to SEQ ID NO : 15 of Morgan et al (see below).
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Morgan et al teach “the chimeric TCR comprises a constant region comprising an amino acid sequence of at least the extracellular domain of a constant region of a murine TCR….. the chimeric TCR can comprise a constant region comprising any of SEQ ID NOs: 4 to 6, or a combination thereof, …… ” ([0038], page 3-4). The SEQ ID NO: 12 of the claimed invention is 100% identical to SEQ ID NO : 6 of Morgan et al (see below).
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Claim 51 is rejected under 35 U.S.C. 103 as being unpatentable over Morgan et al (Pub. No.: US 2009/0304657 A1, Pub. Date: Dec. 10, 2009) in view of Ishikura et al (THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 285, NO. 31, pp. 23916–23924, July 30, 2010, DOI 10.1074/jbc.M110.127936) as applied to claims 43-49 above, and further in view of Wang et al (Pub. No .: US 2022/0280566 A1, Foreign Application Priority Data Apr. 16 , 2019)
The teachings of Morgan et al and Ishikura et al above are incorporated herein in their entirety.
Morgan et al and Ishikura et al do not teach a signal peptide-variable region such as CD8α. Wang et al cure the deficiency.
Regarding to claim 51, Wang et al teach “the extracellular domain further includes a signal peptide and or a hinge region to form a signal peptide- antigen recognition region and hinge region connected in sequence” ([0055], page 3), and “Preferably, the signal peptide is selected from a CD8α signal peptide and or the hinge region is selected from a CD8α hinge region .” ([0056], page 3)
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the engineered TCRs as taught by the above references by including a signal peptide to form a signal peptide- antigen recognition region as taught by Wang et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Wang et al teach “method for optimization and modification of CAR-T, in which all lysine sites in an intracellular segment of CAR are mutated into arginine, thereby blocking ubiquitination modification of the CAR after antigen challenge…. and in particular provides a solution to the problem of poor proliferation of CAR - T in solid tumors” (Abstract) and “Studies have demonstrated that enhancing the proliferative capacity of CAR-T cells in vivo can significantly improve the efficacy of CAR-T therapy, both in hematologic tumor therapy and solid tumor therapy, which provides a direction to optimize CAR-T design” ([0003], page 1). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Wang et al were successful in mutating all lysine sites in an intracellular segment of CAR into arginine and effectively inhibiting the degradation of CAR.
Claims 60-61 are rejected under 35 U.S.C. 103 as being unpatentable over Morgan et al (Pub. No.: US 2009/0304657 A1, Pub. Date: Dec. 10, 2009) in view of Ishikura et al (THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 285, NO. 31, pp. 23916–23924, July 30, 2010, DOI 10.1074/jbc.M110.127936)
Regarding to claim 60, Morgan et al teach “A method of improving the biological activity of a human TCR is further provided by the invention. The method comprises replacing the constant region of the human TCR with a constant region comprising at least an extracellular domain of a constant region of a non-human TCR” ([0013], page 1). Morgan et al teach “The alpha and beta chains of functional variant chimeric TCRs shown in Table 7 are constructed using over lapping PCR techniques. Briefly, a forward primer that matches the 5' of the variable region and a reverse primer that contains the mutation in the constant region are used. The amplified product of this reaction is then used in a second PCR reaction as part of the template DNAs with the same forward primer and a reverse primer at the 3' of the constant region. The full length TCR is then cloned and sequenced to verify the mutation” ([0187], page 18).
Although Morgan et al teach the alpha and beta chains of functional variant chimeric TCRs contains the mutation in the constant region, Morgan et al do not teach a mutated TCR α chain intracellular constant region, wherein the mutated TCR a chain intracellular constant region is a wild-type TCR a chain intracellular constant region with at least one serine mutated to alanine. Ishikura et al cure the deficiency.
Ishikura et al teach “serine residues in the cytosolic tail of the T-cell antigen receptor α-chain mediate ubiquitination and endoplasmic reticulum-associated degradation of the unassembled protein” (Title). Ishikura et al teach “The T-cell antigen receptor (TCR) α-chain (TCR α) is a type I integral membrane protein that becomes ubiquitinated and targeted to the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway when it fails to assemble into the heteromeric TCR complex. Remarkably, TCR α has a cytosolic tail of only five amino acid residues (i.e. RLWSS), none of which is the conventional ubiquitin acceptor, lysine. Herein we report that substitution of two conserved serine residues in the cytosolic tail of TCR α to alanine decreased ubiquitination, whereas placement of additional serine residues enhanced it. Moreover, replacement of the cytosolic serine residues by other ubiquitinatable residues (i.e. cysteine, threonine, or lysine) allowed ubiquitination to take place. Serine-dependent ubiquitination perfectly correlated with targeting of TCR α for ERAD. We also found that this ubiquitination was mediated by the ER-localized ubiquitin ligase, HRD1. These findings indicate that serine-dependent, HRD1-mediated ubiquitination targets TCR α to the ERAD pathway” (Abstract)
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior arts to modify the method of Morgan et al by mutating TCR α chain intracellular constant region (a cytosolic tail) with at least one serine mutated to alanine as taught by Ishikura et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Ishikura et al teach “FIGURE 1. Mutation of two serine residues in the cytosolic tail of TCRα inhibits its ubiquitination and degradation.” (page 23918, Figure 1) and “The results presented here show that TCRα ubiquitination and ERAD targeting are dependent on two serine residues, Ser- 267 and Ser-268, in the cytosolic tail of TCRα. Substitution of these serine residues to alanine decreased ubiquitination of TCRα (Fig. 1), whereas placement of additional serine residues enhanced it (Figs. 2 and 3). Moreover, substitution of the serine residues by other ubiquitinatable residues (i.e. cysteine, threonine, or lysine) allowed ubiquitination to take place (Fig. 4)” (see page 23921, Discussion, right column, 3rd para. ). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Ishikura et al were successful in mutating two serine residues in the cytosolic tail of TCRα that inhibits its ubiquitination and degradation.
Regarding to claim 61, Morgan et al teach “…the constant region of the chimeric TCR can comprise an extracellular domain, a transmembrane domain, and an intracellular domain of a constant region of a murine TCR. In this respect, the chimeric TCR can comprise a constant region comprising any of SEQ ID NOs: 4 to 6,…” ([0038]), page 4). ), and “Alternatively or additionally, the chimeric TCR can comprise an α chain of a TCR and a β chain of a TCR. Each of the α chain and β chain of the inventive chimeric TCR can independently comprise any amino acid sequence.” ([0040], page 4). The SEQ ID NO: 3 of the claimed invention is 100% identical to SEQ ID NO : 4 of Morgan et al (see below).
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Conclusion
No claim is allowed.
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/KHOA NHAT TRAN/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632
