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 1-15 are cancelled.
Applicant’s election without traverse of an RBD derived from the soluble part of an envelope glycoprotein of a primate T-lymphotropic virus (PTLV) (from claim 23), an RBD derived from a human T-cell leukemia virus type 2 (HTLV-2) (from claims 24 and 31), a conventional CD8+ T cell (from claims 28 and 33) in the reply filed on 03/06/2026 is acknowledged.
Claims 16-35 are pending and under examination on the merits.
Priority
This application is a 371 of PCT/EP2021/080796, filed 11/05/2021, which claims priority to EUROPEAN PATENT OFFICE (EPO) Application No. 20306327.6, filed 11/05/2020. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
IDS
The information disclosure statement (IDS) filed 08/09/2023 has been considered.
Claim Interpretation
Recitations preceded/modified by the term ‘optionally’ are not deemed to be required by the claim(s), as presently drafted.
Recitations of a GLUT1 ligand and RBD are being interpreted to be synonymous, as is consistent with page 4 of the instant specification.
Recitations of “high” and “low” are being interpreted to be consistent with the disclosure at pages 18-19 of the specification.
Claim Objections
Claim 17 is objected to because of the following informalities: “quantifying the binding” in line 4 should read “quantifying binding”.
Claim 21 is objected to because of the following informalities: for claim 21, the preamble of the claim fails to correlate with the body of the claim. The body of the claim recites “contacting T cells with a glucose transporter 1 (GLUT1) ligand for selecting T cells with improved anti-cancer activity”. However, the body of the claim does not recite a step for or criteria by which selection, as recited in the preamble, is to occur within the metes and bounds of the claim. In order to remove any possible ambiguity the claim should also include a step of selection and criteria for said selection. It is recommended to include a step in the body of the claim which correlates the observed results of a selected cell having improved anti-cancer activity with the selection method steps. Method claims should clearly set forth the various method steps in a positive, sequential manner using active tense verbs such as mixing, reacting and detecting. Method steps should clearly state each component used in the method and the relationship of the various components, and should not be a mere cataloging of parts. The claims should also conclude with a step relating the method result to the purpose of the method, preferably to the purpose as also set forth in the preamble of the claim.
Claim 27 is objected to because of the following informalities: for claim 27, the preamble of the claim fails to correlate with the body of the claim. The body of the claim recites “monitoring glucose transporter 1 (GLUT1) as a biomarker of anti-cancer therapeutic efficacy of T cells”. However, the body of the claim does not recite a step for or criteria by which determining an anti-cancer therapeutic efficacy of T cells, as recited in the preamble, is to occur within the metes and bounds of the claim. In order to remove any possible ambiguity the claim should also include a step of determining and criteria for said determination. It is recommended to include a step in the body of the claim which correlates the observed results of a determining an anti-cancer therapeutic efficacy of T cells with the method steps recited in the body (specifically, how said determination is made and based on what; presently, the only required step is monitoring GLUT1). Method claims should clearly set forth the various method steps in a positive, sequential manner using active tense verbs such as mixing, reacting and detecting. Method steps should clearly state each component used in the method and the relationship of the various components, and should not be a mere cataloging of parts. The claims should also conclude with a step relating the method result to the purpose of the method, preferably to the purpose as also set forth in the preamble of the claim.
Appropriate correction is required.
35 U.S.C. 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 16-19 and 20-35 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. The claim is directed to a judicial exception (a correlation which is a natural phenomenon), specifically, the selection of Glut1-low (GLUT1Lo) T cells and the property of improved anti-cancer activity. Furthermore the claim does not integrate said judicial exception in to practical application, and the claim does not recite additional elements that amount to significantly more than said judicial exception.
Where a claim describes a judicial exception, such a claim “requires closer scrutiny for eligibility because of the risk that it will ‘tie-up’ the excepted subject matter and pre-empt others from using [the judicial exception]" (federal register, p.74622, C1). While all inventions to some degree involve natural laws, products, and other judicial exceptions, the new guidance regarding patent eligibility makes clear that a practical application of these exceptions is necessary, offering “significantly more” than the exception itself. Limitations that were found not to be enough to qualify as “significantly more” include:
Mere instructions to implement an abstract idea on a computer;
Adding generic instructions that the judicial exception should be used ("apply it");
Simply appending well-understood, routine and conventional activities previously known to the industry, specified at a high level of generality;
Adding insignificant extra solution activity to the exception ("mere data gathering"); and
Generally linking the use of the exception to a particular technological environment or field of use.
The MPEP (see § 2103-2106.07) provides a means of determining whether a particular claim is patent eligible under 35 U.S.C. 101. The Guidance requires an analysis of multiple steps, Steps 1, 2A, and 2B:
Step 1 - Following a determination of the broadest reasonable interpretation of a claim, is the claim drawn to a process, machine, manufacture, or composition of matter? If the answer to this inquiry is “Yes,” the analysis moves on to step 2A.
Step 2A - A two-prong analysis. For prong one, does the claim recite an abstract idea, law of nature, or natural phenomenon? If “Yes,” the analysis proceeds to prong two, which asks whether the claim recites additional elements that integrate the judicial exception into a practical application. If “No,” the analysis moves on to step 2B.
Step 2B - Does the claim recite additional elements that amount to significantly more than the judicial exception? If “No,” the claim is not eligible subject matter under 35 U.S.C. 101.
In the instant case, the claims are drawn to a process, so the answer to Step 1 is “Yes.”
With respect to prong one of Step 2A, the answer is “Yes,” because as indicated above, the claims are drawn to a natural phenomenon.
Claim 16 is directed to a method of selecting T cells based having a low measured GLUT1 expression, said low expression being associated with improved anti-cancer activity.
Claim 17 only substantively adds that the GLUT1 expression measured is on the surface of the T cell. Claim 18 defines the meaning of low expression. Claim 19 narrows that the measuring/quantifying is done by FACS. Claims 22-26 merely narrow the type of ligand. Claims 28-29 merely narrow the T cell population. Claim 30 merely narrows the cancer. Thus, claims 17-19, 22-26, and 28-30 incorporate and fail to remedy the deficiency of claim 16, from which they depend.
Claim 20 recites selecting the cells with improved anti-cancer activity of claim 16 and administering a therapeutic amount of the cells to a subject as part of a method for treating cancer.
Claim 31 recites that the GLUT1 ligand comprises an RBD from a Markush group of viral sources. Claim 32 narrows that the RBD comprises or consists of SEQ ID NO:15. Claim 33 narrows the T cells to particular phenotypes. Claim 34 adds that the T cells are CAR T cells. Claim 35 narrows the type of cancer intended to be treated. Thus, claims 31-35 incorporate and fail to remedy the deficiency of claim 20, from which they depend.
Claim 21 is a substantively broader recitation of instant claim 16, requiring selection of T cells after contact with a GLUT1-Ligand (the only described material includes selection of T cells measured to have low GLUT1 expression) and noting that the only steps required are selection and contacting, where selection is a mental step.
Claim 27 is directed towards a method of determining an anti-cancer therapeutic efficacy of T cells, comprising monitoring glucose transporter 1 (GLUT1) as a biomarker of anti-cancer therapeutic efficacy of T cells (noting that only supported/disclosed/described embodiments pertain to monitoring for low GLUT1 expression and subsequent selection of said GLUT1Lo T cells as having an anti-cancer therapeutic efficacy.
Regarding claim 16, the claim language reciting the judicial exception is found in the preamble and step b (requiring selection based on a GLUT1 level associated with improved ant-cancer activity) where step a merely requires quantifying a glucose transporter 1 (GLUT1) level, which is extrasolution activity).
Step 1 - Following a determination of the broadest reasonable interpretation of a claim, is the claim drawn to a process, machine, manufacture, or composition of matter? If the answer to this inquiry is “Yes,” the analysis moves on to step 2A. Here, the instant claim 16 recites, “A method of selecting….” Therefore, the instant claim 16 is directed towards a method, which is a process under 35 U.S.C. 101. So the answer to step 1 is “YES.” Thus, the analysis proceeds to Step 2A.
Step 2A - A two-prong analysis. For prong 1, does the claim recite an abstract idea, law of nature, or natural phenomenon? If “Yes,” the analysis proceeds to prong 2, which asks whether the claim integrates the judicial exception into a practical application. If “No,” the analysis moves on to step 2B. Here, the instant claim 16 includes step b directed to a mental step of selecting cells, which is a judicial exception based on a natural correlation of GLUT1 expression and anti-cancer activity, which is a natural phenomenon, which is a judicial exception. Therefore, the answer to prong 1 of step 2A is “YES.” Thus, the analysis proceeds to prong 2 of step 2A. Here, the instant claim 16 fails to recite any claim limitations which would integrate the recited judicial exception, for example, by applying or using said judicial exception to affect a particular treatment or prophylaxis for a disease or medical condition.
Step 2B - Does the claim recite additional elements that amount to significantly more than the judicial exception? If “No,” the claim is not eligible subject matter under 35 U.S.C. 101.
The additional claim elements are insufficient to amount to significantly more than the judicial exception for the following reasons.
Simply appending well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, has been found to be insufficient to add “significantly more” (MPEP 2106.05(I)(A)).
The additional step a of quantifying GLUT1 expression at the cell surface of a T cell or population thereof amounts to no more than mere data gathering steps and does not add ‘significantly more,’ (see Mayo v. Prometheus, 566 U.S.66, 132 SA. Ct. 1289). The claims fail to include additional elements that are sufficient to amount to significantly more than the judicial exception(s) recited in step b (including the subsequent wherein clause).
Therefore, the answer to prong 2B is “No” and the instant claim 16 is therefore directed toward patent ineligible subject matter under 35 U.S.C. 101 and is therefore rejected under 35 U.S.C. 101.
Dependent claims 17-19, 22-26, and 28-30, via dependency, incorporate the noted judicial exceptions of claim 16 (discussed above), are directed to processes, and fail to add significantly more or to integrate said judicial exceptions such as by a treatment step.
Regarding claim 20, the claim language reciting the judicial exception is found in the lines 2-3, which refer back to claim 16 which requires quantifying a glucose transporter 1 (GLUT1) level, which is extrasolution activity).
Step 1 - Following a determination of the broadest reasonable interpretation of a claim, is the claim drawn to a process, machine, manufacture, or composition of matter? If the answer to this inquiry is “Yes,” the analysis moves on to step 2A. Here, the instant claim 16 recites, “A method of selecting….” Therefore, the instant claim 16 is directed towards a method, which is a process under 35 U.S.C. 101. So the answer to step 1 is “YES.” Thus, the analysis proceeds to Step 2A.
Step 2A - A two-prong analysis. For prong 1, does the claim recite an abstract idea, law of nature, or natural phenomenon? If “Yes,” the analysis proceeds to prong 2, which asks whether the claim integrates the judicial exception into a practical application. If “No,” the analysis moves on to step 2B. Here, the instant claim 20 depends from and, thereby, incorporates, claim 16 which includes step b directed to a mental step of selecting cells, which is a judicial exception based on a natural correlation of GLUT1 expression and anti-cancer activity, which is a natural phenomenon, which is a judicial exception. Therefore, the answer to prong 1 of step 2A is “YES.” Thus, the analysis proceeds to prong 2 of step 2A. Here, the instant claim 20 fails to recite any claim limitations which would integrate the recited judicial exception, for example, by applying or using said judicial exception to affect a particular treatment or prophylaxis for a disease or medical condition. While claim 20 does recites administering to the subject a therapeutic amount of T cells with improved anti-cancer activity, this is not deemed to integrate the judicial exception due to the high level of generality with which the administration step is recited. From MPEP 2106.05(f): Another consideration when determining whether a claim integrates a judicial exception into a practical application in Step 2A Prong Two or recites significantly more than a judicial exception in Step 2B is whether the additional elements amount to more than a recitation of the words “apply it”...(3) The particularity or generality of the application of the judicial exception. A claim having broad applicability across many fields of endeavor may not provide meaningful limitations that integrate a judicial exception into a practical application or amount to significantly more. For instance, a claim that generically recites an effect of the judicial exception or claims every mode of accomplishing that effect, amounts to a claim that is merely adding the words “apply it” to the judicial exception.
So little detail is provided regarding the subject and/or administration that the recited administration step amounts to no more than a suggestion to apply the cells of claim 16, doing no more to integrate the claim to a limited, practical application.
Step 2B - Does the claim recite additional elements that amount to significantly more than the judicial exception? If “No,” the claim is not eligible subject matter under 35 U.S.C. 101.
The additional claim elements are insufficient to amount to significantly more than the judicial exception for the following reasons.
Simply appending well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, has been found to be insufficient to add “significantly more” (MPEP 2106.05(I)(A)).
The selection step is purely a mental step (a further judicial exception) and the administration step is recited at such a high level of generality that is does not reasonably add ‘significantly more,’ (see Mayo v. Prometheus, 566 U.S.66, 132 SA. Ct. 1289). The claims fail to include additional elements that are sufficient to amount to significantly more than the judicial exception(s) recited in step b (including the subsequent wherein clause).
Therefore, the answer to prong 2B is “No” and the instant claim 20 is therefore directed toward patent ineligible subject matter under 35 U.S.C. 101 and is therefore rejected under 35 U.S.C. 101.
Dependent claims 31-35, via dependency, incorporate the noted judicial exceptions of claim 20 (discussed above), are directed to processes, and fail to add significantly more or to integrate said judicial exceptions.
Regarding claim 21, the claim language reciting the judicial exception is found in lines 1-3 of the claim, where the recitation of selection is a mental step based upon contacting T cells with a GLUT1 ligand (where the only supported/described/disclosed embodiment is selection of T cells having low GLUT1 expression because of the association of low GLUT1 expression and improved anti-cancer activity).
Step 1 - Following a determination of the broadest reasonable interpretation of a claim, is the claim drawn to a process, machine, manufacture, or composition of matter? If the answer to this inquiry is “Yes,” the analysis moves on to step 2A. Here, the instant claim 21 recites, “A method of selecting….” Therefore, the instant claim 21 is directed towards a method, which is a process under 35 U.S.C. 101. So the answer to step 1 is “YES.” Thus, the analysis proceeds to Step 2A.
Step 2A - A two-prong analysis. For prong 1, does the claim recite an abstract idea, law of nature, or natural phenomenon? If “Yes,” the analysis proceeds to prong 2, which asks whether the claim integrates the judicial exception into a practical application. If “No,” the analysis moves on to step 2B. Here, the instant claim 21 includes the recitation of selection, which is a mental step, which is a judicial exception, based upon contacting T cells with a GLUT1 ligand (where the only supported/described/disclosed embodiment is selection of T cells having low GLUT1 expression because of the association of low GLUT1 expression and improved anti-cancer activity which represents a correlation which is a natural phenomenon which is a judicial exception). Therefore, the answer to prong 1 of step 2A is “YES.” Thus, the analysis proceeds to prong 2 of step 2A. Here, the instant claim 21 fails to recite any claim limitations which would integrate the recited judicial exception, for example, by applying or using said judicial exception to affect a particular treatment or prophylaxis for a disease or medical condition.
Step 2B - Does the claim recite additional elements that amount to significantly more than the judicial exception? If “No,” the claim is not eligible subject matter under 35 U.S.C. 101.
The additional claim elements are insufficient to amount to significantly more than the judicial exception for the following reasons.
Simply appending well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, has been found to be insufficient to add “significantly more” (MPEP 2106.05(I)(A)).
The additional step a of contacting a T cell or population thereof with a GLUT1 ligand (disclosed and understood to be part of a step of measurement/quantification of GLUT1) amounts to no more than mere data gathering steps and does not add ‘significantly more,’ (see Mayo v. Prometheus, 566 U.S.66, 132 SA. Ct. 1289). The claims fail to include additional elements that are sufficient to amount to significantly more than the judicial exception(s) recited in lines 1-3.
Therefore, the answer to prong 2B is “No” and the instant claim 21 is therefore directed toward patent ineligible subject matter under 35 U.S.C. 101 and is therefore rejected under 35 U.S.C. 101.
Regarding claim 27, the claim language reciting the judicial exception is found in lines 1-3 of the claim, where the recitation of determining is a mental step based upon monitored GLUT1 (associated with anti-cancer therapeutic efficacy (where the only supported/described/disclosed embodiment is determination of T cells having low GLUT1 expression as having relatively better anti-cancer therapeutic efficacy because of the association of low GLUT1 expression and improved anti-cancer activity/therapeutic efficacy)).
Step 1 - Following a determination of the broadest reasonable interpretation of a claim, is the claim drawn to a process, machine, manufacture, or composition of matter? If the answer to this inquiry is “Yes,” the analysis moves on to step 2A. Here, the instant claim 27 recites, “A method of determining….” Therefore, the instant claim 27 is directed towards a method, which is a process under 35 U.S.C. 101. So the answer to step 1 is “YES.” Thus, the analysis proceeds to Step 2A.
Step 2A - A two-prong analysis. For prong 1, does the claim recite an abstract idea, law of nature, or natural phenomenon? If “Yes,” the analysis proceeds to prong 2, which asks whether the claim integrates the judicial exception into a practical application. If “No,” the analysis moves on to step 2B. Here, the instant claim 27 includes the recitation of determining, which is a mental step, which is a judicial exception, based upon monitoring GLUT1 expression (where the only supported/described/disclosed embodiment is determination of T cells having low GLUT1 expression as having relatively better/greater anti-cancer therapeutic efficacy because of the association of low GLUT1 expression and improved anti-cancer activity/ therapeutic efficacy which represents a correlation which is a natural phenomenon which is a judicial exception). Therefore, the answer to prong 1 of step 2A is “YES.” Thus, the analysis proceeds to prong 2 of step 2A. Here, the instant claim 27 fails to recite any claim limitations which would integrate the recited judicial exception, for example, by applying or using said judicial exception to affect a particular treatment or prophylaxis for a disease or medical condition.
Step 2B - Does the claim recite additional elements that amount to significantly more than the judicial exception? If “No,” the claim is not eligible subject matter under 35 U.S.C. 101.
The additional claim elements are insufficient to amount to significantly more than the judicial exception for the following reasons.
Simply appending well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, has been found to be insufficient to add “significantly more” (MPEP 2106.05(I)(A)).
The additional step a of monitoring GLUT1 as a biomarker of anti-cancer therapeutic efficacy of T cells amounts to no more than mere data gathering steps and does not add ‘significantly more,’ (see Mayo v. Prometheus, 566 U.S.66, 132 SA. Ct. 1289). The claims fail to include additional elements that are sufficient to amount to significantly more than the judicial exception(s) recited in lines 1-3.
Therefore, the answer to prong 2B is “No” and the instant claim 27 is therefore directed toward patent ineligible subject matter under 35 U.S.C. 101 and is therefore rejected under 35 U.S.C. 101.
Therefore, claims 16-19 and 21-30 are rejected under 35 USC §101 as being directed towards patent ineligible judicial exceptions ( mental steps and/or natural phenomenon, failing to integrate or add substantially more so as to transform the metes and bounds of the claims into subject matter eligible for patentability.
Claim Rejections - 35 USC § 112
35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
Claims 16-35 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
The purpose of the written description requirement is to ensure that the inventor had possession, at the time the invention was made, of the specific subject matter claimed. To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B. V. v. Dianwnd Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
The Application claims broad genera of GLUT1-binding RBDs and/or ligands binding GLUT1 and cancers for which the claimed T cells have anti-cancer activity/therapeutic efficacy and does not provide evidence that the claimed RBDs/ligands as broadly recited would function to bind as claimed or that all cancers would function in the methods as claimed. While the table spanning pages 38-42 of the specification provides a certain number of examples of RBDs/ligands (SEQ ID NOs: 5-12 (HTLV1); SEQ ID NOs: 13-16 (HTLV2); SEQ ID NOs: 17-18 (HTLV3); SEQ ID NOs: 19-21 (HTLV4); SEQ ID NOs: 22-23 (STLV1); SEQ ID NOs:24-25 (STLV2); SEQ ID NOs: 26-27 (STLV3); SEQ ID NO: 28-STLV5; SEQ ID NOs: 29-31 H2 RBD; and SEQ ID NOs: 32-52 representing ligands/RBDs), it is noted that many of the sequences are to the same ligand/RBD with a minor variation (such as being attached to GFP or a rabbit or murine Fc region). Moreover, it is clear that there is no demonstrated consensus sequence of sequence associated with the claimed function(s) (no structure-function correlation) and the genera are extremely broad (noting that a cloned derivative could, arguably, be highly mutated and still fall within the claims as drafted because no structure is required by the claims). Therefore, in view of this disclosure, Applicant is claiming broad genera of RBDs/Ligands and cancers without a representative number of species of said genera. The cancer in/for which the methods disclosed are disclosed and described to function for is leukemia (see examples 1-7 at pages 44-49). While Applicant names a number of cancers (see pages 29-31 of the instant specification), the only cancer the disclosure describes as functioning in the methods claims is leukemia. The specification does not provide adequate written description for the entire claimed genus of species of RBDs/ligands as claimed, because in the absence of empirical determination, one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed. The genera of RBDs and ligands each encompass a wide variety of structurally distinctly biological classes, such as proteins/peptide, aptamers, and antibodies. The specification does not reasonably provide a descriptive, representative number of species or a structure-function correlation that would allow the artisan to readily envisage the members of the genera claimed that would function as claimed in the methods recited by the instant claims.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. Applicant has only fully disclosed the sequences of the table at pages 38-42 (sequences 5-52) noting the structural heterogeneity and noting that some of the sequences merely reflect the same RBD attached to a GFP or rabbit or murine Fc region) for consideration. Thus, given the substantial structure variation within the genera as well as the high level of unpredictability in the art, the disclosure of a limited number of species having little to no apparent structural/sequential overlap is not sufficiently representative of the entire genus claimed (encompassing RBDs and/or ligands not described or even invented).
Furthermore, Applicant has not disclosed relevant, identifying characteristics of amino acid or nucleic acid sequences that confer upon an RBD or ligand the ability to function as claimed because the instant specification does not provide structural antibody features that correlate with an ability to function as required by the claimed methods.
Absent a clear description of the at least minimal structural features correlating with a functional ability to function as claimed which are shared by members of a genus commonly sharing this function, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish which members of the recited genera would possess the ability to function as claimed.
Regarding antibody RBDs/ligands, while the prior art teaches some understanding of the structural basis of antigen-antibody and/or receptor-binding domain/ligand recognition, it is noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains. For example, Al Qaraghuli et al (2020, Nature Scientific Reports 10:13969), state that the six CDRs form a continuous surface to form the paratope that binds the epitope of the cognate antigen (that is, the 6 CDRs interact to form the portion of the antibody responsible for binding). Note that the broad recitation of a GLUT1 ligand encompasses an antibody (see for example, pages 3 bridging 4 of the instant specification). This suggests that a change in the CDR sequence may result in a conformationally different paratope which may fail to bind target as claimed. Here, a mutation in the CDRs may result in a paratope unable to bind GLUT1. Rabia et al (2018, Biochemical Engineering Journal 137:365-374) teach what effects mutations can have on an antibody's stability, solubility, binding affinity and binding specificity. Rabia et al report that an increase in antibody affinity can be associated with a decrease in stability (p. 366, col. 2 last paragraph; Fig. 2). Tiller et al (2017, J. Biol. Chem. (2017) 292(40) 16638–16652) and Tsuji et al (2022, J Virol 96:e00071-22) teach that mutations in the CDRs (especially HCDR3 are unpredictable and accompanied by tradeoffs in performance (for example increased affinity may lead to decreased specificity); see references in their entirety paying particular attention to the abstract of Tiller et al and the abstract and results section of Tsuji et al). The above cited references underscore the unpredictability of even a single mutation in the CDRs. The instant claims allow for mutations in the CDRs whereupon the mutated paratope may fail to bind GLUT1, as claimed. Thus, the claims need to specify exact CDR sequences of the anti-GLUT1 antibody.
Accordingly, absent empirical determination, one skilled in the art would be unable to predict or envision which CDR sequences comprised within the genus comprising the claimed CDR sequences may be combined/mutated such that the resultant antibody possesses an antigen-binding site capable functioning as claimed. The general knowledge and level of skill in the art does not adequately supplement the omitted description, because specific, not general guidance is needed. Since the disclosure fails to describe relevant, identifying structural characteristics, in the form of fixed heavy and light chain CDR amino acid sequence combinations, that correlate with the ability to function as claimed, and because the one disclosed species detailed above is not sufficient to describe the claimed genus, it is submitted that the written description requirement of 35 U.S.C. 112(a) has not been met.
The claims encompass an antibody binding GLUT1. The specification does not describe which amino acid residues of the antibody are responsible for the functions claimed. Rather, the specification implies that these potential agents must first be screened in an assay to ascertain if the agents have the functions required by the instant claims. Although the specification provides disclosure of a limited number of RBDs/ligands (see the table spanning pages 38-42 of the specification), it fails to disclose the structures common to all members of the genus of antibodies encompassed by the instant claims. The specification does not disclose the structure of all of the encompassed antibodies and fails to disclose which sequences are responsible for the functions claimed. In the absence of a known or disclosed correlation between structure and function, claims which encompass variants defined by their function are generally not considered described.
Applicant is directed to MPEP § 2163 for guidelines on compliance with the written description requirement. Here, applicant has not described a reasonable number of members of the genus of antibodies that would function in the method(s) as claimed, but rather has presented the public with an idea of how to perform an assay that might identify some peptides that fall within the scope of the claim. Of course, depending on what agents are used in the screening assay, it may well identify none. The Court of Appeals for the Federal Circuit addressed claims of this sort in great detail in University of Rochester v. G.D. Searle and Co. (69 USPQ 2nd 1886, CAFC 2004). In Rochester, the Federal Circuit upheld the district court's ruling that patent claims which recited administration of compounds not disclosed, but rather to be identified in a screening assay, were invalid on their face.
In Ariad, the court further noted that the written description plays a particularly important role in the biological arts, where patentees might otherwise be tempted to claim a genus of compounds by its function or result:
“The written description requirement also ensures that when a patent claims a genus by its function or result, the specification recites sufficient materials to accomplish that function—a problem that is particularly acute in the biological arts. 5 See Guidelines for Examination of Patent Applications Under the 35 U.S.C. 112, 1, “Written Description” Requirement, 66 Fed. Reg. 1099, 1105-1106 (Jan. 5, 2001). This situation arose not only in Eli Lilly but again in University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916 [69 USPQ2d 1886] (Fed. Cir. 2004). In Rochester, we held invalid claims directed to a method of selectively inhibiting the COX-2 enzyme by administering a non-steroidal compound that selectively inhibits the COX-2 enzyme. Id. at 918. We reasoned that because the specification did not describe any specific compound capable of performing the claimed method and the skilled artisan would not be able to identify any such compound based on the specification's function description, the specification did not provide an adequate written description of the claimed invention. Id. at 927-28. Such claims merely recite a description of the problem to be solved while claiming all solutions to it and, as in Eli Lilly and Ariad's claims, cover any compound later actually invented and determined to fall within the claim's functional boundaries—leaving it to the pharmaceutical industry to complete an unfinished invention.”
Ariad Pharmaceuticals., Inc. v. Eli Lilly & Co., 94 USPQ2d 1161, 1173 (Fed. Cir. 2010) (en banc). Emphasis added.
The Federal Circuit has clarified Written Description as it applies to antibodies in the recent decision Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. 112(a) (or pre-AIA first paragraph) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called “newly characterized antigen” test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the “newly characterized antigen” test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad, 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of an antigen alone is not considered adequate written description of a claimed antibody to that antigen, even when preparation of such an antibody is routine and conventional. Id.
While generically the structure of antibodies is known, the structure of the presently recited antibodies can vary substantially within the above given claimed recitations. As noted in Amgen, knowledge that an antibody binds to a particular epitope on an antigen tells one nothing at all about the structure of the antibody, wherein “instead of analogizing the antibody-antigen relationship to a ‘key in a lock,’ it [is] more apt to analogize it to a lock and ‘a ring with a million keys on it.” (Internal citations omitted). The relevant antibody art confirms this quandary, indicating that “knowledge of an epitope or antigen used to generate a monoclonal antibody is insufficient for making the original antibody available, even if suitable in vitro test systems for screening are used.” See p. 8, lines 3-5 of WO 2009/033743 A1. Therefore, those of skill in the art would not accept that the inventor had been in possession of the full genus of antibodies in the present claims.
Although screening techniques can be used to isolate CDR variant antibodies that possess the ability to function as claimed, Applicant is reminded that the written description requirement of 35 U.S.C. 112 is severable from the enablement provision. As stated in Vas-Cath Inc. v. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, “The purpose of the 'written description' requirement is broader than to merely explain how to 'make and use'; the applicant must also convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed.”
Applicant is further directed to In re Alonso (545 F.3d 1015 (Fed. Cir. 2008), which involved claims that were directed to methods of using antibodies wherein the court found that the claims lacked adequate written description for the recited genus of antibodies recited in the methods. (C) See p. 8, 3rd paragraph, where Applicant argues that the claims recite all essential features of the invention. Therefore, products used in methods are rightfully subject to the written description requirement.
The recited Glut1 ligand genus and/or RBD genus further encompasses proteins. Regarding the state of the art, Listov et al (Opportunities and challenges in design and optimization of protein function. Nat Rev Mol Cell Biol 25, 639–653 (2024)) teach that the primary amino acid sequence determines downstream structure (protein folding), which then determines function (presenting both the inverse folding problem and the inverse function problem (see for example, Figure 1 and its caption; see also Mishra et al (Inaccurate secondary structure predictions often indicate protein fold switching. Protein Sci. 2019 Aug;28(8):1487-1493. doi: 10.1002/pro.3664. Epub 2019 Jun 17)). Expanding on these problems in proteomics, Reardon (Nature 635, 246-248 (2024)) explains that the goal of designing a protein with known and predictable function, binding partners, size, location, and other traits is, for the moment, a dream. Reardon teaches that further challenges in protein design include predicting how a protein, even if it binds to target, will function upon said binding. Reardon teaches that the primary structure (amino acid sequence) of a protein is critical to function, noting that even proteins of similar shape do not execute the same functions, while those with different shapes may carry out the same tasks. Reardon goes on to teach that it is not always apparent which parts of the primary sequence are important; a seemingly useless amino-acid chain on the side of an enzyme, for instance, might affect how tightly a protein can bind to other molecules or its ability to flip between conformational states. Moreover, Reardon explains that when researchers attempt to solve the structure of a protein experimentally, they often end up seeing only the most stable conformation, which is not necessarily the form the protein takes when it is active (see for example, pages 246-247 of Reardon).
Regarding the aptamer RBDS/ligands encompassed by the claims, Lee et al (Biomedicines. 2023 Jan 26;11(2):356. doi: 10.3390/biomedicines11020356) teach that most aptamers are developed via in silico design and that, while aptamers can be designed that bind to complex polymers such as small molecules or proteins, with the current technology level, it is impossible to design aptamers that bind to cells (see for example, page 2 of 22). Likewise, Bruno et al (Molecules. 2015 Apr 16;20(4):6866-87. doi: 10.3390/molecules20046866) teach that, while there are rare cases in which one can engineer effective bidentate or multidentate aptamers, if detailed knowledge of proximal epitopes and their spacing on complex targets is available, but in general, natural selection will probably produce superior affinity or avidity and specificity (see for example, section 2.1 at page 6869).
Regarding the genus of cancers encompassed by the claims, the art teaches the heterogeneity of cancers and lack of a universal cure (see Allison et al (Heterogeneity and Cancer, retrieved from: https://www.cancernetwork.com/view/heterogeneity-and-cancer (2014) at exemplary paragraph 1 of the Introduction) and American Cancer Society (Can Cancer be Cured?, American Cancer Society, retrieved from: https://www.cancer.org/cancer/understanding-cancer/can-cancer-be-cured.html)(2021)).
Therefore, the genera of RBDs/ligands and cancers encompassed by the instant claimed are only disclosed by function/insufficient structure, without a representative number of species or unifying, conserved structure clearly enabling one skilled in the art to readily envisage the members of the genera claimed which would function as claimed in the claimed method(s). Therefore, claims 16-35 are deemed to fail to meet the written description requirement, as presently drafted.
Enablement
Claims 20 and 31-35 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating leukemia or esophageal squamous cell cancer (ESCC; in light of the prior art, discussed below), does not reasonably provide enablement for treating other cancers or all cancers. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
MPEP 2164.01(a) states that in order to determine compliance with the enablement requirement, the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is “reasonable” or is “undue.”
These factors include but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The breadth of the claims
Claims 20 and 31-35 are broadly directed to a method for treating cancer.
The nature of the invention
Claims 20 and 31-35 are broadly directed to a method for treating cancer. The claims are directed to biological subject matter which is understood to be complex and often unpredictable.
The state of the prior art
The state of the prior art supports that cancer represents a heterogenous genus of disease with no universal cure (see Allison et al (Heterogeneity and Cancer, retrieved from: https://www.cancernetwork.com/view/heterogeneity-and-cancer (2014) at exemplary paragraph 1 of the Introduction) and American Cancer Society (Can Cancer be Cured?, American Cancer Society, retrieved from: https://www.cancer.org/cancer/understanding-cancer/can-cancer-be-cured.html)(2021)).
The level of one of ordinary skill
As the claims are directed to treatment of cancer, the artisan is presumed to be highly skilled, tending to have an advanced degree (such as a Ph.D. or an M.D.).
The level of predictability in the art
The state of the prior art supports that cancer represents a heterogenous genus of disease with no universal cure (see Allison et al (Heterogeneity and Cancer, retrieved from: https://www.cancernetwork.com/view/heterogeneity-and-cancer (2014) at exemplary paragraph 1 of the Introduction) and American Cancer Society (Can Cancer be Cured?, American Cancer Society, retrieved from: https://www.cancer.org/cancer/understanding-cancer/can-cancer-be-cured.html)(2021)). Zhang et al (J Immunol. 2018 Oct 1;201(7):2165-2175. doi: 10.4049/jimmunol.1800230. Epub 2018 Aug 27; citation 9 under NPL on the 08/09/2023 IDS) support that selection of GLUT1Lo T cells exhibit improved anti-cancer activity in esophageal squamous cell cancer (ESCC) when used in adoptive T cell therapy/a HER2-CAR T cell. Therefore, the predictability of any single cure to function for all cancers would be extremely unpredictable and is not enabled by the prior art.
(F) The amount of direction provided by the inventor
Applicant only discloses examples and data pertaining to the anti-cancer activity/therapeutic efficacy of GLUT1Lo T cells or GLUT1lo CAR T cells in leukemia models. No other data or guidance as to which cancers would be treated by such cells/CAR T cells is reasonable understood to be provided to enable the large breadth of cancers encompassed by the claimed genus (see for example, pages 29-31 of the instant specification).
The existence of working examples
Applicant only discloses examples and data pertaining to the anti-cancer activity/therapeutic efficacy of GLUT1Lo T cells or GLUT1lo CAR T cells in leukemia models (see for example, Examples 1-7 at pages 44-49).
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
The case is directed to biological subject matter, which is by nature complex. There are no working example provided for cancers other than leukemia and the state of the art fails to step in to provide enablement where the instant disclosure is lacking. The artisan would be forced into burdensome experimentation so as to effectively invent what applicant only suggests may be possible.
Thus, in light of the contradictory findings in the prior art, the instant disclosure is not enabling for a method of treating all cancers, but is deemed enabled for treating leukemia or ESCC.
35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 17, 26, and 32 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.
Regarding claim 17, step c, recited as optional and therefore not required by the claim, is not sufficiently defined so as to be clearly distinct from the selection recited in step b. The specification appears to describe, employ, and, by example, define the terms select and isolate to encompass identical processes of exemplary, but non-limiting, magnetic sorting flow cytometric embodiments. Artisans are left to dispute whether the selection step is a mental step or something more and are further left to determine whether select and isolation are the same step or somehow different steps. It is unclear how optional step C alters the claim scope.
Regarding claim 26, the claim recites the open language “comprising,” which does not exclude additional unrecited elements. Claim 26 also recites the closed language “consisting of”, which does not allow for additional unrecited elements. (see MPEP § 2111.03). Therefore, it is unclear how the scope of claim 26 allows for additional unrecited elements and how it can also exclude additional unrecited elements. One of ordinary skill in the art would not be reasonably apprised of the scope of patent protection sought. For example, it is unclear in regards to claim 26 which recites “comprising or consisting of the amino acid of SEQ ID NO: 15”, if the patent protection sought is limited to the recited sequence (e.g., Seq ID No: 15) or the sequence recited in the context of any sequence.
Regarding claim 27, it is unclear what cell Applicant intends for the GLUT1 to be monitored on. Artisans are left to dispute 1) whether monitoring means something different than quantifying/measuring (in which case, there is no definition of descriptive example provided by Applicant which may create concerns regarding 35 USC §112(a)) or is synonymous with recitations of quantifying/measuring and 2) what cell type or sample the GLUT1 is being monitored on (CD8+ T cells? cancer cells? etc.). The metes and bounds of the claim are indefinite as drafted because artisans must devise and dispute what is encompassed by and would infringe the claim as drafted.
Regarding claim 32, the claim recites the open language “comprising,” which does not exclude additional unrecited elements. Claim 32 also recites the closed language “consisting of”, which does not allow for additional unrecited elements. (see MPEP § 2111.03). Therefore, it is unclear how the scope of claim 32 allows for additional unrecited elements and how it can also exclude additional unrecited elements. One of ordinary skill in the art would not be reasonably apprised of the scope of patent protection sought. For example, it is unclear in regards to claim 32 which recites “comprising or consisting of the amino acid of SEQ ID NO: 15”, if the patent protection sought is limited to the recited sequence (e.g., Seq ID No: 15) or the sequence recited in the context of any sequence.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 16-35 is/are rejected under 35 U.S.C. 103 as being unpatentable over Battini et al (US 20150133363 A1) in view of Zhang et al (J Immunol. 2018 Oct 1;201(7):2165-2175. doi: 10.4049/jimmunol.1800230. Epub 2018 Aug 27; citation 9 under NPL on the 08/09/2023 IDS)
Regarding claim 16, Battini et al teach ligands/RBDs that bind to GLUT1 (see for example, the abstract). Battini et al teach that these ligands/RBDs may be derived from HTLV2 or PTLV (see for example, paragraphs 0008 and 0016 at page 1 and paragraphs 0042-0043 at page 3). Battini et al further teach a method comprising: a) collecting sample from a subject, b) determining the level of GLUT1 expression at a cell surface using an isolated polypeptide wherein said polypeptide is a soluble receptor binding domain (RBD) ligand derived from the soluble part of the glycoprotein of a primate T-lymphotropic virus binding to the Glucose Transporter 1 (GLUT1), and c) comparing said level to a reference value (see for example, paragraph 0019 at page 1), where said method may relate to diagnosing disease and the disease may be cancer (see for example, paragraphs 0019-0023 at page 1). Battini et al teach that methods for determining and/or quantifying binding of a RBD ligand on GLUT1 on the surface of a cell are well known by the skilled artisan (noting that GLUT1 expression is measured on a population of 293T cells, see for example paragraph 0275 at page 15). They include but are not limited to flow cytometry (see for example, paragraphs 0039-0040 at page 3).
Battini et al do not teach selection or use of T cells with low GLUT1 expression for improved anti-cancer activity.
However, Zhang et al teach that CD8+ T cells play an important role in the adaptive immune response to eliminate intracellular pathogens and cancer cells. These CD8+ cell can develop into memory T (Tm) cells (understood to read upon the recited conventional CD8+ T cells, in light of the lack of a closed definition provided by the instant specification (see page 25 of the specification)). Zhang et al teach further that studies have showed that T cells that survive for a prolonged time and that are less differentiated display superior antitumor ability than the terminal-differentiated effector cells. Metabolism reprogramming through limiting glycolysis or promoting mitochondrial metabolism during priming allows more cells to enter the Tm cell pool. Therefore, Zhang et al hypothesized that targeting genes associated with glycolysis to regulate Tm cell differentiation is possible to enhance the antitumor effects of T cells. Zhang et al teach that miRNAs are involved in the genome-wide regulation of gene expression in humans, including the development of cancers. Dynamic expression of miRNAs has been demonstrated in Tn, Teff, and memory CD8+ T cells during T differentiation, where single miRNAs have been linked with the regulation of CD8+ T cell differentiation (see for example, page 2165). Zhang et al isolated Tn (CD45RA+CD62L+), Teff (CD45RA+CD62L−), and Tcm (CD45RA−CD62L+) cell subgroups from 10 healthy volunteers. To verify the role of miR-143 (suspected to inhibit GLUT1 expression on the T cell, thereby decrease/inhibiting glycolysis) in T cell differentiation, we overexpressed or downregulated miR-143 in CD8+ T cells by transducing T cells with miR-143 mimics or inhibitor, respectively. Fluorescence signals of FITC on CD8+ T cells analysis indicated a nearly 85% transfection efficiency. Overexpression/transfection with miR-143 promotes the generation of CD8+ Tcm cells. Zhang et al further teach that Both the mRNA (p < 0.05) and protein levels of Glut-1 were decreased by miR-143 overexpression and were increased by miR-143 suppression (p < 0.01; Fig. 4C, 4D). Zhang et al further detected the expression of miR-143 and Glut-1 in ESCC cancer tissues and adjacent normal tissues. The expression of miR-143 was lower in cancer tissues than in adjacent normal tissues (p < 0.01; Fig. 4E), whereas the expression of Glut-1 was higher in cancer tissues than in adjacent normal tissues (p < 0.01; Fig. 4F). These results indicated that Glut-1 is the important target gene of miR-143 and might be involved in T cell differentiation (see for example, page 2167). We analyzed the phenotype and function of CD8+ T cells with or without Glut-1 siRNA. Tm cells were significantly increased in the Glut-1 siRNA group (Fig. 5A). In addition, Glut-1 siRNA significantly increased the expression level of the memory potential biomarkers CD27 and CD28 (p < 0.01) and decreased the terminally differentiated effector cell biomarker PD-1 (p < 0.01) in CD8+ T cells and Tcm cells (Fig. 5B, 5C). Importantly, Glut-1 siRNA significantly increased the release of cytokines IFN-γ and IL-2 in CD8+ T cells (Fig. 5D). These results support that the role of miR-143 in regulating T cell differentiation and its antitumor effect depend on Glut-1 (see for example, pages 2167-2168 at the section titled Glut-1 regulates the differentiation of Tn cells to fully functional memory CD8+ T cells and page 2171 [discussing results that indicate that miR-143 enhances CD8+ T cell memory potential and antitumor function by inhibiting glycolytic metabolism]).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. The artisan would have been motivated to make and use the invention, quantifying the GLUT1 cell surface expression level in T cells according the teachings of Battini et al in order to select for T cells having a relatively lower level of GLUT1 expression for use in adoptive therapy/treatment because Zhang et al show that T cells having lower relative GLUT1expression (caused by the miR-143 overexpression) have improved longevity, differentiation to the CD8+ Tm cell type, and improved cytotoxicity (aka anti-cancer activity; see the teachings cited above from Zhang et al). The MPEP provides that:
“The Supreme Court in KSR reaffirmed the familiar framework for determining obviousness as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), but stated that the Federal Circuit had erred by applying the teaching-suggestion-motivation (TSM) test in an overly rigid and formalistic way. KSR, 550 U.S. at 404, 82 USPQ2d at 1391. Specifically, the Supreme Court stated that the Federal Circuit had erred in four ways: (1) “by holding that courts and patent examiners should look only to the problem the patentee was trying to solve ” (Id. at 420, 82 USPQ2d at 1397); (2) by assuming “that a person of ordinary skill attempting to solve a problem will be led only to those elements of prior art designed to solve the same problem” (Id.); (3) by concluding “that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘obvious to try’” (Id. at 421, USPQ2d at 1397); and (4) by overemphasizing “the risk of courts and patent examiners falling prey to hindsight bias” and as a result applying “[r]igid preventative rules that deny factfinders recourse to common sense” (Id.). See also Novartis Pharms. Corp. v. West-Ward Pharms. Int'l Ltd., 923 F.3d 1051, 1059, 2019 USPQ2d 171676 (Fed. Cir. 2019); Apple Inc. v. Samsung Elecs. Co., 839 F.3d 1034, 1047-48, 120 USPQ2d 1400, 1410 (Fed. Cir. 2016); and Aventis Pharma S.A. v. Hospira, Inc., 675 F.3d 1324, 1332, 102 USPQ2d 1445, 1449 (Fed. Cir. 2012)… Importantly, the Supreme Court reaffirmed principles based on its precedent that “[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.”Id. at 415-16, 82 USPQ2d at 1395. The Supreme Court stated that there are “[t]hree cases decided after Graham [that] illustrate this doctrine.” Id. at 416, 82 USPQ2d at 1395. (1) “In United States v. Adams, . . . [t]he Court recognized that when a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result.” Id. (2) “In Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., . . . [t]he two [pre-existing elements] in combination did no more than they would in separate, sequential operation.” Id. at 416-17, 82 USPQ2d at 1395. (3) “[I]n Sakraida v. AG Pro, Inc., the Court derived . . . the conclusion that when a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious.” Id. at 417, 82 USPQ2d at 1395-96 (Internal quotations omitted.). The principles underlining these cases are instructive when the question is whether a patent application claiming the combination of elements of prior art would have been obvious. The Supreme Court further stated that:
When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability. For the same reason, if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond his or her skill. Id. at 417, 82 USPQ2d at 1396.
When considering obviousness of a combination of known elements, the operative question is thus “whether the improvement is more than the predictable use of prior art elements according to their established functions.” Id,”
(see MPEP §2141(I)). The artisan would have found it obvious to try selecting and using GLUT1Lo T cells with a reasonable expectation of achieving the results (improved anti-cancer activity) taught by Zhang et al resulting in the method of Battini et al being modified according to Zhang et al to select for GLUT1Lo T cells having improved anti-cancer activity, resulting in a method meeting the limitations of the instant claim. Note that there is no limiting, closed definition of selection provided. Therefore, a recitation of section may be met by a mental step of selecting these quantified cells, a step of gating during flow cytometric analysis, or by other means known in the art. Here, Battini et al at least teach a mental step of selection (in quantifying the GLUT1 on cells, some sort of mentals groups, reading on selections, are being made-such as GLUT1hi and GLUT1lo) and Zhang et al teach a mental selection step and a step of gating during flow cytometric analysis (see for example, Figure 2 at page 2169), both of which the artisan would have found obvious having been motivated by the reference to select for GLUT1-low CD8+ T cells. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 17, as discussed above, Battini et al discuss measuring/quantifying GLUT1 expression at the surface of a cell, such as a T cell. Battini et al teach a method comprising:
Step a0) contacting a biological sample (such as biopsies or cells or tissue manifesting or with a suspected aberrant GLUT1 expression profile) from an individual with at least one polypeptide of the invention, said at least one polypeptide being optionally labeled, or susceptible to be recognized by a labeled molecule;
Step a1-a2) determining the level of said at least one polypeptide bound to the cells contained in the biological sample and comparison with the level of binding of said compound to cells contained in the biological sample from an healthy individual (see for example, paragraphs 0213-0215 at column 2 of page 12). As discussed above, the artisan would have been motivated to modify the method of Battini et al according to Zhang et al in order to select for T cells having improved anticancer activity. As noted in the rejection under 35 USC §112(b) above, Applicant has not distinguished the difference between recited steps of selecting and steps of isolating. Further, step c is drafted to be optional and is not required to meet the claim as drafted. However, as discussed above Zhang et al isolated Tn (CD45RA+CD62L+), Teff (CD45RA+CD62L−), and Tcm (CD45RA−CD62L+) cell subgroups from 10 healthy volunteers (see for example, page 2167). Note that the step of quantifying binding of the GLUT1 ligand (step a1) is being interpreted as consistent with page 7 of the instant specification (detecting that the RBD/ligand has bound/complexed with GLUT1) and the recitation of quantifying GLUT1 expression level (step a2) is being interpreted as consistent with page 19 of the instant specification (where the expression level is performed/quantified by FACs (understood by the artisan to be a type of flow cytometry). As discussed in the rejection above, there are no steps and no limited closed definition of selection. Therefore, the cited teachings of Battini et al and Zhang et al make obvious selection of GLUT1Lo cells wither by mental selection and/or by flow cytometric gating, rendering obvious step b.
Regarding claim 18, the artisan, looking to select for GLUT1Lo T cells from a sample population would have found it obvious to first select for GLUT1+ cells, and to the select for cells in the population with relatively lower GLUT1 for use in subsequent adoptive immunotherapy (see for example, page 2173 of Zhang et al), with selection of 50% or lower of the cells having relatively lower GLUT1 expression being an obvious starting point, which further lower % selection (i.e.: selection of the 30% lowest GLUT1 expression cells) being routine optimization of a result effective variable. As noted in In re Aller, 105 USPQ 233 at 235, more particularly, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Routine optimization is not considered inventive and no evidence has been presented that arriving at the selection of 50% or lower (having the lowest relative surface GLUT1 expression) of the cells GLUT1+ T cells was anything other than routine, that the properties of the selected T cells from the optimization has any unexpected properties, or that the results should be considered unexpected in any way as compared to the closest prior art. Optimization of parameters is a routine practice that would be obvious for the artisan to employ. See MPEP § 2144.05. The artisan would have had a reasonable expectation of success based on the cumulative disclosure of the combined prior art references before the effective filing date of the invention and therefore would have found it prima facie obvious to arrive at a method meeting the limitations of the instant claim.
Regarding claim 19, as discussed above, Battini et al teach that methods for determining and/or quantifying binding of a RBD ligand on GLUT1 on the surface of a cell are well known by the skilled artisan (noting that GLUT1 expression is measured on a population of 293T cells, see for example paragraph 0275 at page 15). They include but are not limited to flow cytometry (see for example, paragraphs 0039-0040 at page 3).
Regarding claim 20, as discussed above, Zhang et al teach that CD8+ Tm cells transfected/overexpressing miR-143 (understood to reduce GLUT1 expression/function and thereby reduce glycolysis) have improved anti-cancer activity (improved longevity/persistence, improved differentiation to a Tm phenotype, and improved cytotoxic activity (such as cytokine production/secretion)) see for example, pages 2167-2168 at the section titled Glut-1 regulates the differentiation of Tn cells to fully functional memory CD8+ T cells and page 2171 [discussing results that indicate that miR-143 enhances CD8+ T cell memory potential and antitumor function by inhibiting glycolytic metabolism]). This would have led the artisan to understand that T cells having reduced/low Glut1 would likely exhibit these desirable anti-cancer features in the setting of ESCC, motivating the artisan to select for GLUT1Lo CD8+ T cells from a patient sample for use in adoptive therapy for ESCC (cancer) (see for example, page 2173 of Zhang et al). The artisan would understand that adoptive therapy must be administered to the subject in order for the cells to exert a therapeutic effect in the subject. The artisan would have found it obvious to use GLUT1LO CD8+ T cells to reduce the number of steps/reagents/labor and cost to achieve the effects shown and taught by Zhang et al and would have found it obvious to use a prior art method to screen for and select GLUT1Lo CD8+ T cells from the subject’s sample, such as the method of Battini et al, for autologous adoptive therapy for cancer using cells with an improved anticancer activity.
Battini et al and Zhang et al do not explicitly discuss “a therapeutic amount” of the T cells.
However, doses and dosage regimens are result effective variables. It is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989) (determination of suitable dosage amounts in diuretic compositions considered a matter of routine experimentation and therefore obvious).
As both doses and dosage regimens were known to the ordinary artisan, it would have been obvious to optimize the dose and/or regimen to achieve a therapeutic effect (therefor being a therapeutic amount as defined in the specification at page 28-where Applicant further defined a therapeutic amount noting that “The above parameters for assessing successful treatment and improvement in the disease are readily measurable by routine procedures familiar to a physician”, indicating agreement between Applicant and the Examiner that the therapeutic amount would have been an obvious matter for routine optimization well within the ability of the artisan to determine).
It is not inventive to discover the optimum or workable ranges by routine experimentation, In re Aller, 220 F.2d 454, 456 (CCPA; see also In re Peterson, 315, F.3D, 1325 (Fed. Cir. 2003).
Only if the results of optimizing a variable are unexpectedly good can a patent be obtained for the claimed critical ranges, In re Geisler, 116 F.3d 1465, 1469, (Fed. Cir. 1997) quoiting in re Antoine, 559 F.2d 618, 620 (CCPA 1977)
Discovery for an optimum value or a result effective variable in a known process is ordinarily with the skill of the art. In re Boesch 617 F,2d 272, 276 (CCPA 1980).
Regarding claim 21, as discussed above Zhang et al teach that CD8+ GLTU1Lo T cells have improved anti-cancer activity in the setting of ESCC, motivating the artisan to select for GLTU1Lo CD8+T cells. The artisan would have found it obvious to use a prior art method for measuring/quantifying GLUT1 surface expression on the T cells, such as the method of Battini et al, thus making obvious the steps of contacting the T cells with a GLUT1 ligand and selecting GLUT1Lo CD8+ T cells to select for cells with improved anti-cancer activity.
Regarding claim 22, as discussed above, Battini et al teach that the GLUT1 ligand may be optionally labeled, or susceptible to be recognized by a labeled molecule (see for example, paragraphs 0213-0215 at column 2 of page 12).
Regarding claim 23, as discussed above, Battini et al teach that the GLUT1 ligand/RBD may be derived from the soluble part of the glycoprotein of the enveloped virus of Primate T-cell leukemia virus (PTLV) (see for example, the abstract).
Regarding claims 24-26 and 31-32, Battini et al teach that the GLUT1 ligand/RBD may be derived from the soluble part of the glycoprotein of the enveloped virus of Primate T-cell leukemia virus (PTLV), which may be an HTLV2-derived RBD, which may comprise SEQ ID NO: 5 (see for example, the abstract and claims 1-2). Note that SEQ ID NO: 5 of Battini et al is 100% identical to instantly claimed SEQ ID NO: 15 (see the alignment provided below).
PNG
media_image1.png
752
1756
media_image1.png
Greyscale
Regarding claim 27, as discussed above, the combination of Battini et al and Zhang et al teach and make obvious motivation to measure/quantify GLUT1 surface expression on CD8+ T cells to select for GLUT1Lo CD8+ T cells (deemed to read on ‘monitoring GLUT1 as a biomarker’ in the absence of a clear, closed, and preclusive definition of what is meant by ‘monitoring GLUT1 as a biomarker’) of anti-cancer therapeutic efficacy of T cells. It is noted that it is unclear what cell Applicant intends for the GLUT1 to be monitored on. However, in the interest of advancing prosecution and to resolve issues of clarity while avoiding concerns of new matter, monitoring is being interpreted as measuring/quantifying GLUT1 on the surface of CD8+ T cells using FACS, as this is the only support in the specification for monitoring GLUT1 expression (see for example, page 45 of the instant specification; see also the rejection under 35 USC §112(b) above). Note further that there is no support for monitoring for an overexpression or GLTU1-high CD8+ T cells. Therefore, the substance of claim 27 overlaps with the substance of claim 26 and is made obvious by the same teachings for the same references.
Regarding claims 28 and 33, as discussed above, the cells selected in the combined prior art method reading on the method of instant claims 16 and 20 are CD 8+ Tm cells or cytotoxic cells, which are conventional CD8+ T cells as defined by Applicant (see for example, the claim interpretation section above). Alternatively, where Battini et al and Zhang et al merely name that the selection and quantification work for the surface of a cell, and a CD8+ T cell and only go on to discuss CD8 Tm cells in detail as desirable, the artisan would have understood that the method would work for quantifying and selecting conventional CD8+ T cells.
Regarding claims 29 and 34, as discussed above, the combination of Battini et al and Zhang et al teach and make obvious the method of instant claims 16 and 20, wherein the CD8+ GLUT1Lo selected T cells are HER2 CAR T cells because Zhang et al teach that HER2 CAR T cells with miR-143 overexpression (causing reduced GLUT1 activity) exhibit improved anti-cancer activity (see for example, page 2167 and Figs. 3G-I with their respective captions at page 2170). The artisan would understand that, as the claim does not specify whether GLUT1 is measured/quantified and selected for before or after generation of the CAR T cell, GLUT1 is measurement/quantification and selection would be expected to reliably select for GLUT1Lo CD8+ T cells having improved anti-cancer activity at either point (before or after CAR generation), yielding no more than predictable results, the timepoint of selection therefore being a matter of obvious choice.
Regarding claims 30 and 35, as discussed above, Battini et al and Zhang et al make teach and make obvious the method of instant claims 16 and 20 for ESCC, which the artisan would have understood is a solid tumor cancer.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Alizadeh et al (Cancer Immunol Res (2019) 7 (5): 759–772; https://doi.org/10.1158/2326-6066.CIR-18-0466) teach that CAR-T cells that are less differentiated and less exhausted are more therapeutically effective and demonstrate that CAR-T cells expanded in IL15 (CAR-T/IL15) preserve a less differentiated stem cell memory (Tscm) phenotype. CAR-T/IL15 cells exhibited decreased mTORC1 activity, reduced expression of glycolytic enzymes and improved mitochondrial fitness. CAR-T/IL2 cells cultured in rapamycin (mTORC1 inhibitor) shared phenotypic features with CAR-T/IL15 cells, suggesting that IL15-mediated reduction of mTORC1 activity is responsible for preserving the Tscm phenotype. CAR-T/IL15 cells promoted superior antitumor responses in vivo in comparison with CAR-T/IL2 cells. IL15 reduced GLUT1 expression in CAR-T cells (see for example, the abstract at page 759 and column 1 of page 764).
Cretenet et al (Scientific Reports, 6:24129,DOI: 10.1038/srep24129; citation 5 under NPL on the 08/09/2023 IDS) teach that surface GLUT1 expression was monitored by binding to the GLUT1 ligand fused to eGFP where the ligands and uses there of taught by Kinet et al (Retrovirology. 2007 May 15;4:31. doi: 10.1186/1742-4690-4-31), teaching a c-terminal antibody against GLUT-1 and GFP-tagged RBDs from HTLV1 and 2 for quantification (high versus low) of surface GLUT1 expression in T cells (see for example paragraph 1 of the Flow cytometry analyses and cell sorting section of page 11 of Cretenet et al and the incorporated title and abstract at page 1 and figures 1 and 2 and their captions at pages 3-4 of Kinet et al).
Singer et al (Int. J. Cancer, 128: 2085-2095. https://doi.org/10.1002/ijc.25543; Epub 2010) teach that high expression of glucose-transporter 1 (GLUT-1) correlates with low CD81 T-cell infiltration in the tumor in renal cell carcinoma (RCC).
The ISA written opinion for PCT/EP2021/080796 (2022; Obtained from: https://patentscope.wipo.int/search/docs2/pct/WO2022096659/pdf/BC2f5H1id_AjjJBIZdNPYTmTsAtsAZrr8W6fAxHmzTTkRu09dtNAzKl4Cm3XzyTjj) discusses the state of the prior art. Sources labeled D7-D11 are deemed most relevant to the claimed subject matter.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ASHLEY GAO whose telephone number is (571) 272-5695. The examiner can normally be reached on M-F 9:00 am - 6:00 pm EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s
supervisor, Gregory Emch can be reached on (571) 272-8149. The fax phone number for the
organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent
Application Information Retrieval (PAIR) system. Status information for published applications
may be obtained from either Private PAIR or Public PAIR. Status information for unpublished
applications is available through Private PAIR only. For more information about the PAIR
system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR
system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would
like assistance from a USPTO Customer Service Representative or access to the automated
information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
Prosecution Insights