DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The claim listing filed March 10, 2026 is pending.
Claims 1, 2, 5, 7, 10-23 are canceled.
Claims 3, 4, 6, 8, 9, and 24-34 are pending.
Claims 32-34 are new claims.
Claims 3 and 4 are independent claims.
Election/Restriction
Applicant’s election with traverse to the invention of Group II (claims 3, 4, 6, 8, 9, and 24-31, drawn to methods of treating a cancer in a human subject in need thereof by administering a therapeutically effective dose of chimeric antigen receptor (CAR) T cells); and without traverse to the species of (a) PGF as the one or more inflammation-related soluble factors and (b) a CAR comprising a costimulatory signaling domain comprising the intracellular signaling domain from 4-1BB and a transmembrane domain from CD8 in the reply filed on March 10, 2026 is acknowledged.
Claims 3, 4, 6, 8, 9, and 24-34 are currently under consideration.
Claim Objections
Claims 4, 6, 25, and 26 are objected to because of the following informalities:
Claim 4 recites “human subject diagnosed with cancer a therapeutically effective dose” where it should recite “human subject diagnosed with the cancer a therapeutically effective dose” in line 2.
Claims 6 and 26 recite “PGF” where it should recite “placental growth factor (PGF)” in line 2.
Claim 25 recites “wherein the plurality of control subject comprise subjects who are responsive to a dose chimeric antigen receptor (CAR) T cells” where it should recite “wherein the plurality of control subjects comprise subjects who are responsive to a dose of chimeric antigen receptor (CAR) T cells” in lines 1 and 2.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
Indefinite Language
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 3, 4, 6, 8, 9, and 24-34 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 3 recites “a control level” in lines 4 and 5 and “the control level” in line 6; claim 24 recites “the control level” in line 1 and “a plurality of control subjects” in lines 2 and 3; and claim 25 recites “the plurality of control subjects” in lines 1 and 2. Claims 3, 24, and 25 are indefinite since the controls are not defined. Without a specific control, each change in the one or more inflammation-related soluble factors is meaningless and indefinite and so the claims are rejected here. Said another way, the controls encompassed are open to multiple structural interpretations and this set of multiple interpretations gives the actual efficacies recited different interpretations, rendering the claims indefinite. Each control should be recited as a specific serum level of the one or more inflammation-related soluble factors and a specific subject that has been treated a specific way.
Calling out the control level by a nonspecific amount of the one or more inflammation-related soluble factors and the control subjects irrespective of how they have been treated is useless because of the variations in the level of these one or more inflammation-related soluble factors and how the control subjects have been treated previously thus rendering the levels and subjects required by the claims indefinite.
It is recommended that claims 3, 24, and 25 be amended to specifically define the controls and how they are measured.
Claims 4 recites “determined to be similar to a level” in line 4. The term “similar” in line 4 is a relative term which renders the claim indefinite. The term “similar” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Therefore, the level of the one or more inflammation-related soluble factors in the serum of the subjects has been rendered indefinite.
Amending claim 4 to recite an specific degree of similarity for the level of the one or more inflammation-related soluble factors in the serum of the subjects would obviate this part of the rejection.
Claim 4 also recites “a level of the one or more inflammation-related soluble factors in a serum sample from a subject responsive to chimeric antigen receptor (CAR) T cells” in lines 5 and 6. It is unclear if the subject that is responsive to CAR T cells is responsive to the same CAR T cells as those being administered to the human subject. It is also unclear what kind of subject the control subject it is. The subject may be a human subject or any other subject. Furthermore, it is unclear if the level of the one or more inflammation-related soluble factors in the subject that is responsive to CAR T cells is meant to be measured before or after the administration of the CAR T cells. For these reasons, claim 4 is indefinite.
Amending claim 4 to recite “a level of the one or more inflammation-related soluble factors in a serum sample from a human subject responsive to the chimeric antigen receptor (CAR) T cells prior to the administration of the CAR T cells” would obviate this part of the rejection.
Claims 4 and 25 recite “a subject responsive to chimeric antigen receptor (CAR) T cells” and “subjects who are responsive to a dose chimeric antigen receptor (CAR) T cells,” respectively. It is unclear what the term “responsive” in the claims means or what the “response” actually is. The term “responsive” is not defined by the claim, the specification does not provide a standard for ascertaining what a response is, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Therefore, the subject that is responsive to a dose of CAR T cells has been rendered indefinite.
Amending claims 4 and 25 to recite an specific response to a dose of CAR T cells would obviate this part of the rejection.
Claim 30 recites “wherein the transmembrane domain is or comprises a transmembrane domain from CD8” in lines 3 and 4. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 30 recites the broad recitation “comprises,” and the claim also recites “is” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Amending claim 30 to recite “wherein the transmembrane domain is a transmembrane domain from CD8” or “wherein the transmembrane domain comprises a transmembrane domain from CD8” would obviate this part of the rejection.
Claim 31 recites “the antigen binding domain” in line 2. Claim 31 depends on claims 1 and 28 which recite “an extracellular antigen-binding domain” but neither recite “an antigen binding domain.” Therefore, the term “the antigen binding domain” in claim 31 lacks antecedent basis and renders the claim indefinite.
Amending claim 31 to recite “the extracellular antigen-binding domain” would obviate this part of the rejection.
Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 9 and 27-34 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 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.
The instant claims are drawn to (1) a method of treating a cancer in a human subject in need thereof, comprising: a. determining that a level of one or more inflammation-related soluble factors in a serum sample from the human subject in need thereof is at or below a control level, wherein the human subject is selected if the level of one or more inflammation-related soluble factors is at or below the control level; and b. on the basis of the determination in step (a), subsequently providing a therapeutically effective dose of CAR T cells directed to B-cell maturation antigen (BCMA) to the selected human subject in need thereof; and (2) a method of treating a cancer, comprising administering to a human subject diagnosed with cancer a therapeutically effective dose of chimeric antigen receptor (CAR) T cells, wherein a level of one or more inflammation-related soluble factors in a serum sample from the human subject prior to said administration was determined to be similar to a level of the one or more inflammation-related soluble factors in a serum sample from a subject responsive to chimeric antigen receptor (CAR) T cells, wherein the chimeric antigen receptor (CAR) of the CAR T cells comprises an extracellular antigen-binding domain that binds to B-cell maturation antigen (BCMA), a transmembrane domain, and an intracellular signaling region.
Dependent claim 31 limits the anti-BCMA CAR T cells to those that comprises an extracellular spacer between the antigen binding domain and the transmembrane domain, wherein the extracellular spacer is from CD8.
Regarding the genus of anti-BCMA CAR T cells, the Applicant has disclosed an anti-BCMA CAR (BCMA02) with (SEQ ID NO: 9) and without a signal sequence (SEQ ID NO: 37) that comprises the VL and VH amino acid sequences of SEQ ID NOs: 7 and 8, respectively, which respectively comprise the LCDRs1-3 of SEQ ID NOs: 1-3, respectively, and HCDRs1-3 of SEQ ID NOs: 4-6, respectively (e.g. see [0049] – [0053]). It is noted that SEQ ID NO: 38 is the amino acid sequence of the anti-BCMA scFv of the above anti-BCMA CAR.
The Applicant has also disclosed the following anti-BCMA CAR T cells: ABECMA (Ide-cel), JCARH125, JNJ-68284528, P-BCMA-101 (Poseida), PBCAR269A (Poseida), P-BCMA-Allo1 (Poseida), Allo-715 (Pfizer/Allogene), CT053 (Carsgen), Descartes-08 (Cartesian), PHE885 (Novartis), and CTX120 (CRISPR Therapeutics) (e.g. see [0217]).
The Applicant only disclosed one example describing how the pretreatment levels of several soluble factors, including PGF, CD70, TNFRSF4, TNFRSF9, DCN, CD83, IL10, PDCD1, IL12, and NCR1 effected anti-BCMA CAR T cell therapy for multiple myeloma, specifically for ABECMA (Ide-cel) (e.g. see Example 2, [0602] – [0607]).
Regarding the CD8-based extracellular spacer of the CAR, the Applicant has not explicitly disclosed any specific the CD8-based extracellular spacers of the CAR. However, the anti-BCMA CARs above may comprise specific extracellular spacers between the antigen-binding domain and the transmembrane domain. Therefore, the extracellular spacers that are part of these CARs are specifically disclosed by the Applicant. These extracellular spacers may be derived from CD8.
When given the broadest reasonable interpretation in light of specification, the anti-BCMA CAR T cells of the instant invention are defined broadly to be any CAR T cell that binds to BCMA. Dependent claim 31 limits the anti-BCMA CAR T cells to those that comprises any CD8-based extracellular spacer between the antigen binding domain and the transmembrane domain.
It is noted that no claim indicates any structure for the genus of the anti-BCMA CAR T cells.
Dependent claim 31 recites that the CAR of claim 28 “further comprises an extracellular spacer between the antigen binding domain and the transmembrane domain, wherein the extracellular spacer is from CD8” in lines 1-3.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by 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 genus (Federal Register, Vol. 66, No. 4, pages 1099-1111, January 5, 2001, see especially page 1106 column 3). In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted:
“A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.”). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
Regarding the genus of anti-BCMA CAR T cells, it is well known that antigen binding domains of CARs fall in three general categories, either single chain variable fragments (scFvs) derived from antibodies, Fab’s selected from libraries, or natural ligands that engage their cognate receptor (e.g. see Sadelain et al. Cancer Discov. 2013;3(4):388–398, page 389, left column, second paragraph under “CAR TARGETING”). Successful examples in each of these categories have been reported. scFvs derived from murine immunoglobulins are commonly used, as they are easily derived from well-characterized monoclonal antibodies. They, however, may prove to be more immunogenic than Fab’s derived from human libraries or invariant human ligands (e.g. see Sadelain et al. Cancer Discov. 2013;3(4):388–398, page 389, left column, second paragraph under “CAR TARGETING”).
Regarding CARs comprising antibody-derived antigen binding domains, artisans are well aware that knowledge of a given antigen (for instance BCMA) provides no information concerning the sequence/structure of antibodies that bind the given antigen. For example, Edwards et al. (J. Mol. Biol., 2003, 334:103-118) teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences spanning almost the entire heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well, see entire document).
As such, it does not seem possible to predict the sequence/structure of an antibody that binds a given antigen, as there does not appear to be any common or core structure present within all antibodies that gives rise to the function of antigen binding. Further, given data, such as that of Edwards et al., indicating the diversity of sequences in a population of antibodies that bind to a given antigen, no number of species appears to reasonably representative of the breadth of the genus of antibodies that bind the given antigen.
It should be pointed out that it is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antigen binding molecule to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway Jr et al., Immunology, 3rd Edition, 1997 Garland Publishing Inc., pages 3:1-3:11.see entire selection).
Thus, based upon the prior art, skilled artisans would reasonably understand that it is the structure of the CDRs within an antibody which gives rise to the functional property of antigen binding, the epitope to which said CDRs bind is an inherent property which appears to necessarily be present due to conservation of critical structural elements, namely the CDR sequences themselves.
This applies to the instant invention which is drawn to a genus of the anti-BCMA CAR T cells.
Regarding the CD8-based extracellular spacer of the CAR, Bernard and Evgin 2025 (Front. Immunol. 16:1664403, 1-9) teach that the hinge domain, also known as the spacer region, connects the binding domain to the transmembrane domain, and provides the flexibility for the CAR to interact with a specific antigen of interest (e.g. see page 3, right column, second paragraph). The most commonly used hinges are derived from CD8α and CD28 (e.g. see page 3, right column, second paragraph).
Bernard and Evgin also teach that there is no a one-size-fits-all approach to hinge engineering and that optimization is required for each CAR (e.g. see page 5, right column, third paragraph). Understanding the properties of the scFv (i.e. affinity, oligomerization propensity), the position of the target epitope on the antigen and its proximity to the membrane, as well as overall antigen density may help to predict a ‘goldilocks’ hinge identity and length (e.g. see page 5, right column, third paragraph).
Bernard and Evgin also teach that while tumor cells with high antigen density elicited the activation of HER2 CAR T cells with a conventional 45 amino acid CD8α hinge as well as the 34 amino acid truncated hinge, tumor cells with low antigen density selectively activated the longer hinge bearing CAR (e.g. see page 5, left column, second paragraph).
Thus the art ultimately teaches that selecting a extracellular spacer or hinge domain for a given CAR is not predictable and is highly specific for a given CAR in order to maintain antigen binding.
This applies to the instant case where the anti-BCMA CAR T cell may comprise any CD8-based extracellular spacer domain.
Regarding the genus of anti-BCMA CAR T cells, as noted above, the Applicant has disclosed twelve anti-BCMA CAR T cells: BCMA02, ABECMA (Ide-cel), JCARH125, JNJ-68284528, P-BCMA-101, PBCAR269A, P-BCMA-Allo1, Allo-715, CT053, Descartes-08, PHE885, and CTX120. The Applicant has also disclosed the CDR amino acid sequences of BCMA02 (SEQ ID NOs: 1-6). Such a disclosure does not serve to provide sufficient written description of the claimed genus of the anti-BCMA CAR T cells.
The disclosure does not identify sufficient structural features or combination of features which give rise to the function of BCMA binding. Additionally, there does not appear to be any reasonable shared structure present in the genera of recited CAR T cells which gives rise to their functional activity. Ultimately, identifying a CAR T cells on the basis of binding to BCMA rather than by identifying the sequence/structure, namely the CDRs, of the anti-BCMA CAR T cells in question is generally insufficient to provide written description.
The claims are drawn to broad genus of anti-BCMA CAR T cells which are functionally defined by their ability to bind to BCMA without reciting a corresponding structure expected to correlate with this ability as supported by Applicant’s disclosure.
Regarding the CD8-based extracellular spacer of the CAR, it is noted that the twelve anti-BCMA CAR T cells may comprise a CD8-based extracellular spacer. Nonetheless, such a disclosure does not serve to provide sufficient written description of the claimed genus of CD8-based extracellular spacers.
The disclosure does not identify sufficient structural features or combination of features which give rise to the function of permitting BCMA binding by the CAR. Additionally, there does not appear to be any reasonable shared structure present in the genera of recited CD8-based extracellular spacers which gives rise to their functional activity. Ultimately, identifying a CD8-based extracellular domain on the basis of permitting binding to BCMA rather than by identifying the sequence/structure of the CD8-based extracellular domain in question is generally insufficient to provide written description.
The claims are drawn to broad genus of CD8-based extracellular spacers which are functionally defined by their ability to permit binding to BCMA without reciting a corresponding structure expected to correlate with this ability as supported by Applicant’s disclosure.
Thus, there is insufficient written description for the breadth of anti-BCMA CAR T cells and CD8-based extracellular spacers as currently claimed, which are distinct and diverse and do not share a common structure that contributes to a common ability to bind or permit binding to BCMA.
Therefore, in view of the breadth of the claims and the limited disclosure, artisans would reasonably conclude that applicant was not in possession of the full breadth of anti-BCMA CAR T cells or CD8-based extracellular spacers as encompassed by the claims at the time the instant application was filed.
Amending the claims to limit the anti-BCMA CAR T cells to the twelve recited in the specification, or at least their CDRs, and specific CD8-based extracellular spacer amino acid sequences, would obviate this part of the rejection.
Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 3, 4, 6, 8, 9, and 24-34 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 methods of treating multiple myeloma in a human subject in need thereof, comprising:
(1) a. determining that a level of CD83, TNFRSF9 (sCD137 or s4-1BB), PGF, and/or CD70 in a serum sample from the human subject in need thereof is at or below a control level, wherein the human subject is selected if the level of CD83, TNFRSF9 (sCD137 or s4-1BB), PGF, and/or CD70 is at or below the control level; and b. on the basis of the determination in step (a), subsequently providing a therapeutically effective dose of anti-BCMA chimeric antigen receptor (CAR) T cells to the selected human subject in need thereof; and
(2) administering to a human subject diagnosed with multiple myeloma a therapeutically effective dose of anti-BCMA chimeric antigen receptor (CAR) T cells, wherein a level of CD83, TNFRSF9 (sCD137 or s4-1BB), PGF, and/or CD70 in a serum sample from the human subject prior to said administration was determined to be similar to a level of CD83, TNFRSF9 (sCD137 or s4-1BB), PGF, and/or CD70 in a serum sample from a subject responsive to anti-BCMA chimeric antigen receptor (CAR) T cells,
does not reasonably provide enablement for methods of treating any cancer in a human subject in need thereof, comprising:
(1) a. determining that a level of any one or more of any inflammation-related soluble factors in a serum sample from the human subject in need thereof is at or below a control level, wherein the human subject is selected if the level of any one or more of any inflammation-related soluble factors is at or below the control level; and b. on the basis of the determination in step (a), subsequently providing a therapeutically effective dose of any chimeric antigen receptor (CAR) T cells to the selected human subject in need thereof; and
(2) administering to a human subject diagnosed with any cancer a therapeutically effective dose of any chimeric antigen receptor (CAR) T cells, wherein a level of any one or more of any inflammation-related soluble factors in a serum sample from the human subject prior to said administration was determined to be similar to a level of the any one or more of any inflammation-related soluble factors in a serum sample from a subject responsive to any chimeric antigen receptor (CAR) T cells.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The factors considered in determining whether a disclosure would require undue experimentation include:
(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.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP § 2164.01.
Nature of the invention/Breadth of the claims
Independent claim 3 is drawn to a method of treating a cancer in a human subject in need thereof, comprising: a. determining that a level of one or more inflammation-related soluble factors in a serum sample from the human subject in need thereof is at or below a control level, wherein the human subject is selected if the level of one or more inflammation-related soluble factors is at or below the control level; and b. on the basis of the determination in step (a), subsequently providing a therapeutically effective dose of chimeric antigen receptor (CAR) T cells to the selected human subject in need thereof.
Dependent claim 6 limits the one or more inflammation-related soluble factors of claim 3 to PGF.
Dependent claim 8 limits the cancer of claim 3 to multiple myeloma.
Dependent claims 9 and 27 limit the CAR T cells of claim 3 to CAR T cells directed to B-cell maturation antigen (BCMA). Claim 27 specific limits the chimeric antigen receptor (CAR) of the CAR T cells to that which comprises an antibody or antibody fragment that targets BCMA.
Dependent claim 24 limits the control level of claim 3 to a control level that is determined from the average value of the one or more inflammation-related soluble factors in a plurality of control subjects.
Dependent claim 25 limits the plurality of control subjects of claim 24 to a plurality of control subjects comprising subjects who are responsive to a dose chimeric antigen receptor (CAR) T cells.
Dependent claim 28 limits the chimeric antigen receptor (CAR) of the CAR T cells of claim 3 to that which comprises an extracellular antigen-binding domain that binds to B-cell maturation antigen (BCMA), a transmembrane domain, and an intracellular signaling region.
Dependent claim 29 limits the intracellular signaling region of claim 28 to that which further comprises a costimulatory signaling domain, comprising an intracellular signaling domain of 4-1BB.
Dependent claim 30 limits the structure of the CAR of claim 29 to that wherein the costimulatory signaling domain is between the transmembrane domain and a cytoplasmic signaling domain of a CD3-zeta (CD3𝞯) chain, wherein the transmembrane domain is or comprises a transmembrane domain from CD8.
Dependent claim 31 limits the CAR if claim 28 to that which further comprises an extracellular spacer between the antigen binding domain and the transmembrane domain, wherein the extracellular spacer is from CD8.
Dependent claim 32 limits the intracellular signaling region of claim 28 to that which comprises a cytoplasmic signaling domain of a CD3-zeta (CD3𝞯) chain and an intracellular signaling domain of 4-1BB.
Independent claim 4 is drawn to method of treating a cancer, comprising administering to a human subject diagnosed with cancer a therapeutically effective dose of chimeric antigen receptor (CAR) T cells, wherein a level of one or more inflammation-related soluble factors in a serum sample from the human subject prior to said administration was determined to be similar to a level of the one or more inflammation-related soluble factors in a serum sample from a subject responsive to chimeric antigen receptor (CAR) T cells.
Dependent claim 26 limits the one or more inflammation-related soluble factors of claim 4 to PGF.
Dependent claim 33 limits the chimeric antigen receptor (CAR) of the CAR T cells of claim 4 to that which comprises an extracellular antigen-binding domain that binds to B-cell maturation antigen (BCMA), a transmembrane domain, and an intracellular signaling region.
Dependent claim 34 limits the intracellular signaling region of claim 33 to that which comprises a cytoplasmic signaling domain of a CD3-zeta (CD3𝞯) chain and an intracellular signaling domain of 4-1BB.
State of the prior art/Predictability of the art
Regarding the role of inflammation-related factors soluble factors in cancer, Guner and Kim 2019 (J Gastric Cancer. 19(3):254–277) teach that inflammation can be a causative factor in cancer development or can result from a consequence of cancer progression (e.g. see Abstract). Additionally, inflammation can be induced by cancer interventions and/or by the cancer-associated complications and subsequently affect the tumor recurrence, progression, and metastasis (e.g. see page 254, last paragraph). It is important to determine the molecular players involved in the inflammatory response against cancer cells to assess the inflammation status and to devise the best therapeutic strategy (e.g. see page 254, last paragraph).
Guner and Kim also teach that various inflammatory parameters are used to assess the inflammatory status during cancer treatment (e.g. see Abstract). It is important to select the most optimal biomarker among these parameters. Additionally, suitable biomarkers must be examined if there are no known parameters. The levels of C-reactive protein, albumin, lymphocytes, and platelets were the most commonly used laboratory parameters, either independently or in combination with other laboratory parameters and clinical characteristics. Furthermore, the data should be interpreted after adjusting for clinically important variables, such as age and cancer stage (e.g. see Abstract).
Guner and Kim also teach that there is an interest in predicting short- and long-term treatment outcomes (e.g. see paragraph spanning pages 265 and 266). Study aim, selection of parameters, and interpretation of results should be carefully performed and issues associated with the sources of examined material (peripheral blood, tumor lysate, or tumor draining vein) and timing of examination (pre- or immediate post-interventional) are also important. Selection of when, how, and what to measure during the intervention may critically affect the decisions and clinical outcomes. Thus, peri-interventional inflammatory responses in patients with cancer require further exploration by a clinical oncologist (e.g. see paragraph spanning pages 265 and 266).
Ultimately, Guner and Kim teach that it is unpredictable to select specific inflammation-related soluble factors play a role in a given cancer and that these factors need to be carefully determined on a cancer-by-cancer basis.
Regarding the role of inflammation-related factors soluble factors on CAR T cell therapy, Magni et al. 2025 (Haematologica. 110(11):2661-2672) teach that CAR T expansion alone does not ensure therapeutic efficacy and elevated markers of systemic inflammation, such as ferritin and C-reactive protein, are linked to poorer outcomes despite robust expansion (e.g. see Abstract). These markers correlate with reduced cytotoxic CD8+ T cells with central memory features among in vivo expanded CAR T-cell populations, with similar associations observed in manufactured and leukapheresis products. Importantly, patients with high baseline inflammation who achieved significant expansion demonstrated progression-free survival outcomes comparable to those with limited expansion, highlighting the negative impact of inflammation on CAR T-cell efficacy. Interestingly, ferritin and C-reactive protein levels were similar among responding patients, regardless of differences in CAR T expansion. These findings indicate that systemic inflammation is associated with the phenotypic quality of T and CAR T cells. While functional validation is warranted, these results underscore the need to address inflammatory pathways to improve treatment outcomes ( e.g. see Abstract).
Ultimately, Magni et al. teach that inflammation-related soluble factors can greatly affect the efficacy of CAR T cell therapy and that these factors need to be specifically identified and addressed in order to improve treatment outcomes.
The teachings of Guner and Kim and Magni et al. apply to the instant case where the claims are drawn to a method of treating any cancer with any CAR T cell by determining the level of any one or more of any inflammation-related soluble factors.
Regarding the role of inflammation-related factors soluble factors in multiple myeloma specifically (see instant claim 8), Wang et al. 2022 (Int. J. Cancer. 151:1750–1759) teach that changes in serum inflammatory factors occur throughout the onset and progression of multiple myeloma (MM) (e.g. see Abstract). Wang et al. teach a casual association between inflammation and MM (e.g. see page 1758, left column, third paragraph). Specifically, this is partly driven by the five common inflammatory factors: MCP3, VEGF, IL-10, IL-7 and TNF-β. Moreover, vulnerability to MM may also increase IL-17 levels in the prognosis (e.g. see page 1758, left column, third paragraph). Wang et al. also teach that they did not find evidence that CRP or the other inflammatory regulators (see Figure 4) were causally associated with MM (e.g. see paragraph spanning pages 1755 and 1756).
This applies to the instant case where claim 8 is drawn to a method of specifically treating MM with any CAR T cell by determining the level of any one or more of any inflammation-related soluble factors.
Ultimately, Wang et al. teach that it is unpredictable to use any inflammation-related soluble factor to determine whether or not to treat MM with any CAR T cell. In fact, Wang et al. teach a specific inflammation-related soluble factor profile in MM and explicitly teach that there are many inflammation-related soluble factors that are not associated with MM.
Regarding the application of any CAR T cell, Zugasti et al. 2025 (Signal Transduction Targeted Ther. 10:210, 1-51) teach that chimeric antigen receptors (CARs) are engineered receptors consisting of a combination of an endodomain, an anchoring transmembrane domain, and an ectodomain (e.g. see page 2, left column, second paragraph). The latter is a ligand-specific extracellular domain consisting of a single-chain variable-fragment (scFv) region and a hinge. The scFv, which provides antigen specificity, is a fusion protein of the variable regions of the light and heavy chains of immunoglobulins linked by a short flexible peptide linker (e.g. see page 2, left column, second paragraph). Antigen targets include CD19 or BCMA in the treatment of R/R B-cell malignancies and R/R multiple myeloma (MM) (e.g. see paragraph spanning pages 1 and 2).
Ultimately, Zugasti et al. teach that CAR T cell therapy is a targeted therapy, meaning that CARs are designed to comprise ligand-specific extracellular domains that bind a specific target. These targets are highly disease specific given that different antigens are expressed at different sites and levels in different diseases and these antigen targets have highly disparate implications in disease progression. For example, BCMA has proven a good target for treating MM with CAR T cells. Thus, it is unpredictable to treat any cancer with any CAR T cell with no particular cancer or target in mind.
This applies to the instant case where the claims are drawn to a method of treating any cancer with any CAR T cell by determining the level of any one or more of any inflammation-related soluble factors.
Taken together, the art ultimately teaches that (1) it is unpredictable to select specific inflammation-related soluble factors that play a role in a given cancer and that these factors need to be carefully determined on a cancer-by-cancer basis (Guner and Kim); (2) inflammation-related soluble factors can greatly affect the efficacy of CAR T cell therapy and that these factors need to be specifically identified and addressed in order to improve treatment outcomes (Magni et al.); (3) it is unpredictable to use any inflammation-related soluble factor to determine whether or not to treat MM with any CAR T cell (Wang et al.); and (4) CAR T cell therapy is a targeted therapy and it is unpredictable to treat any cancer with any CAR T cell with no particular cancer or target in mind (Zugasti et al.).
Thus, based on the art, it would be unpredictable to one of ordinary skill in the art to use a method of treating any cancer with any CAR T cell by determining the level of any one or more of any inflammation-related soluble factors as encompassed by the breadth of the claims.
Working examples/Guidance in the specification
The Applicant has disclosed only one example of treating a cancer with a CAR T cell by determining the level of one or more inflammation-related soluble factors (e.g. see Example 2, [0602]-[0606]). Specifically, the Applicant discloses the finding of a correlation between high levels of certain soluble factors in multiple myeloma patients prior to ide-cel (an anti-BCMA CAR T cell) treatment and a suboptimal response to the treatment (e.g. see [0602]).
The pretreatment levels of several soluble factors, including PGF, CD70, TNFRSF4, TNFRSF9, DCN, CD83, IL10, PDCD1, IL12, and NCR1 were obtained retrospectively from multiple myeloma patients that were treated with ide-cel in the KarMMA trial (NCT03361748) and were responsive or non-responsive at 3 or 9 months post ide-cel infusion (e.g. see [0603]). The levels of the factors were measured during the screening time period, wherein the screening procedures were completed within 28 days prior to leukapheresis (e.g. see [0603]).
The Applicant discloses that that pretreatment levels of the immunomodulatory factors CD83, TNFRSP9 (sCD137 or s4-1BB), PGF, and CD70, specifically, were elevated in the serum of patients with suboptimal responses (e.g. see [0606] and Figure 2). The Applicant further discloses that these inflammation-related soluble factors may negatively modulate T cell effector functions that are associated with suboptimal response to ide-cel (e.g. see [0606]).
Amount of experimentation necessary
The Applicant only discloses a methods of treating a multiple myeloma with anti-BCMA CAR T cells and that pretreatment levels of the immunomodulatory factors CD83, TNFRSP9 (sCD137 or s4-1BB), PGF, and CD70 may negatively modulate this treatment, yet, the claims are not limited to methods of treating multiple myeloma with an anti-BCMA CAR T cell after the serum levels of CD83, TNFRSP9 (sCD137 or s4-1BB), PGF, and/or CD70 in a human subject were determined to be at, below, or similar to that of a control subject that is known to be responsive to the anti-BCMA chimeric antigen receptor (CAR) T cells.
The claimed methods encompass methods of treating any cancer with any CAR T cell after the serum levels of any one or more of any inflammation-related soluble factors in a human subject were determined to be at, below, or similar to that of a control subject that is known to be responsive to any CAR T cells.
There is insufficient objective evidence that the disclosed methods of treating multiple myeloma with anti-BCMA CAR T cells after the serum levels of CD83, TNFRSP9 (sCD137 or s4-1BB), PGF, and/or CD70 in a human subject were determined to be at, below, or similar to that of a control subject that is known to be responsive to the anti-BCMA chimeric antigen receptor (CAR) T cells can be extrapolated to provide guidance and direction for the claimed method of treating any cancer with any CAR T cell after the serum levels of any one or more of any inflammation-related soluble factors in a human subject were determined to be at or below that of a control subject that is known to be responsive to any CAR T cells.
Thus, based on the content of the disclosure in view of the prior art regarding (1) the unpredictability of selecting specific inflammation-related soluble factors that play a role in a given cancer (Guner and Kim); (2) that inflammation-related soluble factors can greatly affect the efficacy of CAR T cell therapy (Magni et al.); (3) the unpredictability of using any inflammation-related soluble factor(s) to determine whether or not to treat MM with any CAR T cell (Wang et al.); and (4) the unpredictability of treating any cancer with any CAR T cell with no particular cancer or target in mind (Zugasti et al.), a skilled artisan, through extensive trial-and-error experimentation, would have to identify a specific cancer and its suitable CAR T cell target and an inflammation-related soluble factor profile that can be used to identify patients that will be responsive to said cancer treatment with a reasonable expectation of success. This quantity of experimentation goes beyond what is considered “a reasonable degree of experimentation” and constitutes undue further experimentation in order to enable the method for the breadth of what is claimed.
Thus, the specification does not enable one of ordinary skill in the art to use what is claimed and therefore claims 3, 4, 6, 8, 9, and 24-34 are rejected under 35 U.S.C. 112(a).
Amending the claims to limit the cancer to multiple myeloma, the CAR T cells to anti-BCMA CAR T cells, and the inflammation-related soluble factors to CD83, TNFRSP9 (sCD137 or s4-1BB), PGF, and/or CD70 would obviate this part of the rejection.
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.
Claims 3, 4, 8, 9, 24, 25, and 27-34 are rejected under 35 U.S.C. 103 as being unpatentable over Raje et al. 2019 (N Engl J Med. 380:1726-1737, an IDS reference filed 12/06/2023, see supplementary material (Protocol) attached) in view of Locke et al. 2020 (Blood Adv. 4 (19): 4898–4911).
Independent claim 3 is drawn to a method of treating a cancer in a human subject in need thereof, comprising: a. determining that a level of one or more inflammation-related soluble factors in a serum sample from the human subject in need thereof is at or below a control level, wherein the human subject is selected if the level of one or more inflammation-related soluble factors is at or below the control level; and b. on the basis of the determination in step (a), subsequently providing a therapeutically effective dose of chimeric antigen receptor (CAR) T cells to the selected human subject in need thereof.
Dependent claim 8 limits the cancer of claim 3 to multiple myeloma.
Dependent claims 9 and 27 limit the CAR T cells of claim 3 to CAR T cells directed to B-cell maturation antigen (BCMA). Claim 27 specific limits the chimeric antigen receptor (CAR) of the CAR T cells to that which comprises an antibody or antibody fragment that targets BCMA.
Dependent claim 24 limits the control level of claim 3 to a control level that is determined from the average value of the one or more inflammation-related soluble factors in a plurality of control subjects.
Dependent claim 25 limits the plurality of control subjects of claim 24 to a plurality of control subjects comprising subjects who are responsive to a dose chimeric antigen receptor (CAR) T cells.
Dependent claim 28 limits the chimeric antigen receptor (CAR) of the CAR T cells of claim 3 to that which comprises an extracellular antigen-binding domain that binds to B-cell maturation antigen (BCMA), a transmembrane domain, and an intracellular signaling region.
Dependent claim 29 limits the intracellular signaling region of claim 28 to that which further comprises a costimulatory signaling domain, comprising an intracellular signaling domain of 4-1BB.
Dependent claim 30 limits the structure of the CAR of claim 29 to that wherein the costimulatory signaling domain is between the transmembrane domain and a cytoplasmic signaling domain of a CD3-zeta (CD3𝞯) chain, wherein the transmembrane domain is or comprises a transmembrane domain from CD8.
Dependent claim 31 limits the CAR if claim 28 to that which further comprises an extracellular spacer between the antigen binding domain and the transmembrane domain, wherein the extracellular spacer is from CD8.
Dependent claim 32 limits the intracellular signaling region of claim 28 to that which comprises a cytoplasmic signaling domain of a CD3-zeta (CD3𝞯) chain and an intracellular signaling domain of 4-1BB.
Independent claim 4 is drawn to method of treating a cancer, comprising administering to a human subject diagnosed with cancer a therapeutically effective dose of chimeric antigen receptor (CAR) T cells, wherein a level of one or more inflammation-related soluble factors in a serum sample from the human subject prior to said administration was determined to be similar to a level of the one or more inflammation-related soluble factors in a serum sample from a subject responsive to chimeric antigen receptor (CAR) T cells.
Dependent claim 33 limits the chimeric antigen receptor (CAR) of the CAR T cells of claim 4 to that which comprises an extracellular antigen-binding domain that binds to B-cell maturation antigen (BCMA), a transmembrane domain, and an intracellular signaling region.
Dependent claim 34 limits the intracellular signaling region of claim 33 to that which comprises a cytoplasmic signaling domain of a CD3-zeta (CD3𝞯) chain and an intracellular signaling domain of 4-1BB.
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Regarding claims 3, 4, 8, 9, and 33, Raje et al. teach a method of treating multiple myeloma in a human subject in need thereof, comprising administering a therapeutically effective dose of anti-BCMA CAR T cells to the human subject in need thereof (e.g. see Abstract). Regarding claims 27-34, Raje et al.’s anti-BCMA CAR T cells, known as bb2121, comprise an anti-BCMA single-chain variable fragment as the extracellular antigen-binding domain, a CD8 hinge domain, a CD8 transmembrane domain, a CD137 (4-1BB) costimulatory motif, and a CD3-zeta signaling domain (e.g. see page 1727, left column, first paragraph and Supplementary Figure 4-1, copied below).
Raje et al.’s Supplementary Figure 4-1
Raje et al. do not teach that the human subject is selected after determining that a level of one or more inflammation-related soluble factors in a serum sample from the human subject in need thereof is (A) at or below a control level (instant claim 3) or (B) similar to a level of the one or more inflammation-related soluble factors in a serum sample from a subject responsive to chimeric antigen receptor (CAR) T cells (instant claim 4).
Raje et al. also do not teach that the control level of claim 3 is determined from the average value of the one or more inflammation-related soluble factors in a plurality of control subjects (instant claim 24) or that the plurality of control subjects comprising subjects who are responsive to a dose chimeric antigen receptor (CAR) T cells (instant claim 25).
Locke et al. teach that one of the most significant determining factors for durable response to CAR T cell therapy is in vivo CAR T-cell expansion commensurate with pretreatment host systemic inflammation (e.g. see paragraph spanning pages 4905 and 4906). Pronounced inflammatory status, reflected by myeloid activation markers before CAR T-cell infusion, associated negatively with durable efficacy and positively with severe toxicities (e.g. see page 4906, paragraph spanning left and right columns).
Locke et al. also teach that pretreatment serum levels of proinflammatory markers, including IL-6 and ferritin, were prominently and negatively associated with clinical efficacy (e.g. see page 4908, paragraph spanning left and right columns). Concordantly, patients with diminished inflammation markers demonstrated a high durable response rate (>60%) and limited rate of inflammation-driven serious adverse events (CRS and neurotoxicity; <10%) (e.g. see page 4908, paragraph spanning left and right columns).
Ultimately, Locke et al. teach an enhanced proinflammatory state reminiscent of myeloid cell hyperactivity might inhibit the activation, expansion, and/or survival of CAR T cells within the tumor microenvironment, while simultaneously contributing to toxicities, possibly through facilitating excess cytokine production (e.g. see page 4908, paragraph spanning left and right columns).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Raje et al.to incorporate the teachings of Locke et al. to include that the human subject to be treated is selected by determining that a level of one or more inflammation-related soluble factors in a serum sample from the human subject in need thereof is (A) at or below a control level (instant claim 3) or (B) similar to a level of the one or more inflammation-related soluble factors in a serum sample from a subject responsive to chimeric antigen receptor (CAR) T cells (instant claim 4). This is because an enhanced proinflammatory state might inhibit the activation, expansion, and/or survival of CAR T cells within the tumor microenvironment, while simultaneously contributing to toxicities, possibly through facilitating excess cytokine production (Locke et al.).
Given that one of the most significant determining factors for durable response to CAR T cell therapy is in vivo CAR T-cell expansion commensurate with pretreatment host systemic inflammation, pronounced inflammatory status associates negatively with durable efficacy and positively with severe toxicities, and pretreatment serum levels of proinflammatory markers are prominently and negatively associated with clinical efficacy while patients with diminished inflammation markers demonstrated a high durable response rate and limited rate of inflammation-driven serious adverse events (Locke et al.); it would have been obvious to a skilled artisan to specifically select multiple myeloma patients with diminished systemic inflammation for the anti-BCMA CAR T cell treatment taught by Raje et al. with a reasonable expectation of success.
A skilled artisan would reasonably expect that multiple myeloma patients with diminished systemic inflammation would respond better to the anti-BCMA CAR T cell treatment taught by Raje et al. than patients with pronounced inflammatory status given Locke et al.’s teachings that an enhanced proinflammatory state might inhibit the activation, expansion, and/or survival of CAR T cells within the tumor microenvironment, while simultaneously contributing to toxicities, possibly through facilitating excess cytokine production.
Furthermore, given that Locke et al. determined the inflammatory status of a subject by measuring the pretreatment serum levels of proinflammatory markers; it would be obvious to a skilled artisan to determine a multiple myeloma patient’s inflammatory status by also measuring the serum level of one or more inflammation-related soluble factors and comparing it to a control, such as a patient who is responsive to the CAR T cell therapy, and selecting those patients whose serum levels of the one or more inflammation-related soluble factors is at, below, or similar to the control. A patient who is responsive to the CAR T cell therapy would be a good control because a skilled artisan would reasonably expect that if a patient to be treated has an inflammatory status, which is determined by serum levels of proinflammatory markers, that is at, below, or similar to that of a patient that is known to be responsive to the CAR T cell treatment, then the patient to be treated would be more likely to also be responsive to said CAR T cell treatment.
Regarding the limitations recited in claims 24 and 25 which recite that the control level of claim 3 is determined from the average value of the one or more inflammation-related soluble factors in a plurality of control subjects and that that the plurality of control subjects comprising subjects who are responsive to a dose chimeric antigen receptor (CAR) T cells, respectively; it would be obvious to a skilled artisan to determine the control value as an average value of the one or more inflammation-related soluble factors in a plurality of control subjects with a reasonable expectation of success. This is because an average value from a plurality of subjects would be a more reliable indicator of successful CAR T cell treatment because it takes a larger sample of the responsive patient population than just a single patient. A control serum level from single patient would not be as reliable as an average serum level from a plurality of patients because there are a multitude of factors (intrinsic or extrinsic) that may influence said serum level. Using a plurality of control subjects ensures that those intrinsic and/or extrinsic factors have less of an effect on the serum levels of the one or more inflammation-related soluble factors and, therefore, the control serum levels can be more confidently relied upon when selecting a patient population for treatment.
Regarding the limitation in claim 25 which recites that the plurality of control subjects comprising subjects who are responsive to a dose chimeric antigen receptor (CAR) T cells, the reasons for selecting controls as patients who are already known to be responsive to the CAR T cell treatment are outline above. Briefly, a patient who is responsive to the CAR T cell therapy would be a good control because a skilled artisan would reasonably expect that if a patient to be treated has an inflammatory status that is similar to that of a patient that is known to be responsive to the CAR T cell treatment, then the patient to be treated would be more likely to also be responsive to said CAR T cell treatment.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 6 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Raje et al. 2019 (N Engl J Med. 380:1726-1737, an IDS reference filed 12/06/2023, see supplementary material (Protocol) attached) in view of Locke et al. 2020 (Blood Adv. 4 (19): 4898–4911), as applied to claims 3 and 4, respectively, and further in view of Newell and Holtan 2017 (Blood Reviews, 31; 57-62).
Dependent claims 6 and 26 limit the one or more inflammation-related soluble factors of claims 3 and 4, respectively, to PGF.
The combined teachings of Raje et al. in view of Locke et al. pertaining to claims 3 and 4 and the rationale for combining them is outlined in the 103 rejection above.
The combined reference teachings differ from the instant invention by not teaching that the one or more inflammation-related soluble factors is PGF.
Newell and Holtan teach that placental growth factor (PlGF or PGF) appears to be a key regulatory factor involved in controlling inflammatory responses via its VEGF-competitive binding to the VEGF receptors and sFlt-1, through PlGF/VEGF homodimer/heterodimer formation, and through activation of downstream signaling pathways controlling cytokine and chemokine production (e.g. see page 58, left column, fourth paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the combined teachings of Raje et al. in view of Locke et al. as applied to claims 3 and 4, and to incorporate the teachings of Newell and Holtan to include that the one or more inflammation-related soluble factors is PGF.
Given that PGF appears to be a key regulatory factor involved in controlling inflammatory responses; it would have been obvious to a skilled artisan to experiment with using PGF as the one or more inflammation-related soluble factors measured to determine the inflammatory status of the patients in the method of selecting and treating multiple myeloma patients as taught by Raje et al. in view of Locke et al with a reasonable expectation of success.
Combining prior art elements according to known methods to yield predictable results is obvious to one of ordinary skill in the art (see MPEP § 2143(A)). From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 3, 4, 8, 9, 24, 25, and 27-34 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-75 of U.S. Application No. 18/707,136 (the ‘136 Application). Although the claims at issue are not identical, they are not patentably distinct from each other.
The instant claims are drawn to a method of treating a cancer in a human subject in need thereof, comprising: a. determining that a level of one or more inflammation-related soluble factors in a serum sample from the human subject in need thereof is at or below a control level, wherein the human subject is selected if the level of one or more inflammation-related soluble factors is at or below the control level; and b. on the basis of the determination in step (a), subsequently providing a therapeutically effective dose of chimeric antigen receptor (CAR) T cells to the selected human subject in need thereof.
The claims in the ‘136 Application are drawn to methods of treating a subject having a multiple myeloma (MM), comprising:(a) determining that a subject has:(i) a serum soluble B cell maturation antigen (sBCMA) level lower than about 600ng/ml; and/or(ii) an absence of IgG heavy chain disease (HCD): and(b) administering to the subject a T cell therapy comprising a dose of genetically engineered T cells expressing a chimeric antigen receptor (CAR) that binds to human BCMA; a method of selecting a subject having a multiple myeloma (MM) for treatment with a T cell therapy comprising a dose of genetically engineering T cells; methods of predicting the response of a subject having a multiple myeloma (MM) to treatment with a T cell therapy comprising a dose of genetically engineered T cells expressing a chimeric antigen receptor (CAR) that binds to human B cell maturation antigen (BCMA); and a method of selecting a subject having a multiple myeloma (MM) for de-bulking.
Regarding the recitation of a “control” in the instant claims, it is noted that while the claims in the ‘136 are silent on the recitation of a control, artisans are well aware controls are used to be compared to a test sample. This applies to the instant case where the claims in the ‘136 application recite that the level of the sBCMA (an inflammatory factor) is lower than a reference (or control) value. A skilled artisan would be well aware that the recited reference values are controls in which the test samples are being measured against.
Thus, the methods of treating a subject having a multiple myeloma (MM) in the ‘136 Application are species of the generic method of treating cancer of the instant claims. It has been held that a generic invention is “anticipated” by a “species” within the scope of the generic invention. See In re Goodman, 29, USPQ2d 2010 (Fed. Cir. 1993).
Regarding the claims in the ‘136 Application that are drawn to method of (a) selecting a subject having a multiple myeloma (MM) for treatment with a T cell therapy comprising a dose of genetically engineering T cells, (b) predicting the response of a subject having a multiple myeloma (MM) to treatment with a T cell therapy comprising a dose of genetically engineered T cells expressing a chimeric antigen receptor (CAR) that binds to human B cell maturation antigen (BCMA), and (c) selecting a subject having a multiple myeloma (MM) for de-bulking; it is noted that these claims are intended to be used to identify a multiple myeloma patient population that would be best suited for the anti-BCMA CAR T cell treatment. Therefore, it would be obvious to a skilled artisan to adapt these methods into a method of treating multiple myeloma with a reasonable expectation of success.
Thus, the claims in the ‘136 Application would anticipate and/or would be obvious over the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 3, 4, 24, 25, 33, and 34 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-75 of U.S. Application No. 18/707,136 (the ‘136 Application) in view of Locke et al. 2020 (Blood Adv. 4 (19): 4898–4911).
The instant claims are drawn to a method of treating a cancer in a human subject in need thereof, comprising: a. determining that a level of one or more inflammation-related soluble factors in a serum sample from the human subject in need thereof is at or below a control level, wherein the human subject is selected if the level of one or more inflammation-related soluble factors is at or below the control level; and b. on the basis of the determination in step (a), subsequently providing a therapeutically effective dose of chimeric antigen receptor (CAR) T cells to the selected human subject in need thereof.
The claims in the ‘136 Application are drawn to methods of treating a subject having a multiple myeloma (MM), comprising:(a) determining that a subject has:(i) a serum soluble B cell maturation antigen (sBCMA) level lower than about 600ng/ml; and/or(ii) an absence of IgG heavy chain disease (HCD): and(b) administering to the subject a T cell therapy comprising a dose of genetically engineered T cells expressing a chimeric antigen receptor (CAR) that binds to human BCMA; a method of selecting a subject having a multiple myeloma (MM) for treatment with a T cell therapy comprising a dose of genetically engineering T cells; methods of predicting the response of a subject having a multiple myeloma (MM) to treatment with a T cell therapy comprising a dose of genetically engineered T cells expressing a chimeric antigen receptor (CAR) that binds to human B cell maturation antigen (BCMA); and a method of selecting a subject having a multiple myeloma (MM) for de-bulking.
Thus, the methods of treating a subject having a multiple myeloma (MM) in the ‘136 Application are species of the generic method of treating cancer of the instant claims. It has been held that a generic invention is “anticipated” by a “species” within the scope of the generic invention. See In re Goodman, 29, USPQ2d 2010 (Fed. Cir. 1993).
Regarding the claims in the ‘136 Application that are drawn to method of (a) selecting a subject having a multiple myeloma (MM) for treatment with a T cell therapy comprising a dose of genetically engineering T cells, (b) predicting the response of a subject having a multiple myeloma (MM) to treatment with a T cell therapy comprising a dose of genetically engineered T cells expressing a chimeric antigen receptor (CAR) that binds to human B cell maturation antigen (BCMA), and (c) selecting a subject having a multiple myeloma (MM) for de-bulking; it is noted that these claims are intended to be used to identify a multiple myeloma patient population that would be best suited for the anti-BCMA CAR T cell treatment. Therefore, it would be obvious to a skilled artisan to adapt these methods into a method of treating multiple myeloma with a reasonable expectation of success.
The claims in the ‘136 Application differ from the instant invention by failing to recite that the control level is from a subject responsive to chimeric antigen receptor (CAR) T cells or that the control level is an average value from a plurality of control subjects.
The teachings of Locke et al. are recited above.
It would be obvious to one of ordinary skill in the art to modify the claims in the ‘136 Application and to incorporate the teachings of Locke et al. to specifically use a control level from a subject responsive to chimeric antigen receptor (CAR) T cells and that the control level is an average value from a plurality of control subjects.
Regarding the limitations drawn to a control level from a subject responsive to chimeric antigen receptor (CAR) T cells, given that Locke et al. determined he inflammatory status of a subject by measuring the pretreatment serum levels of proinflammatory markers, such as sBCMA; it would be obvious to a skilled artisan to determine a multiple myeloma patient’s inflammatory status by also measuring the serum level of one or more inflammation-related soluble factors and comparing it to a control, such as a patient who is responsive to the CAR T cell therapy, and selecting those patients whose serum levels of the one or more inflammation-related soluble factors is at, below, or similar to the control with a reasonable expectation of success. A patient who is responsive to the CAR T cell therapy would be a good control because a skilled artisan would reasonably expect that if a patient to be treated has an inflammatory status, which is determined by serum levels of proinflammatory markers, that is at, below, or similar to that of a patient that is known to be responsive to the CAR T cell treatment, then the patient to be treated would be more likely to also be responsive to said CAR T cell treatment.
Regarding the limitations which recite that the control level is determined from the average value of the one or more inflammation-related soluble factors in a plurality of control subjects; it would be obvious to a skilled artisan to determine the control value as an average value of the one or more inflammation-related soluble factors in a plurality of control subjects with a reasonable expectation of success. This is because an average value from a plurality would be a more reliable indicator of successful CAR T cell treatment because it takes a larger sample of the responsive patient population than just a single patient. A control serum level from single patient would not be as reliable as an average serum level from a plurality of patients because there are a multitude of factors (intrinsic or extrinsic) that may affect said serum level. Using a plurality of control subjects ensures that those intrinsic and/or extrinsic factors have a more negligible effect on the serum levels of the one or more inflammation-related soluble factors and, therefore, the control serum levels can be more confidently relied upon when selecting a patient population for treatment.
Therefore, the claims in the ‘136 Application would render the instant claims obvious.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 6 and 26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-75 of U.S. Application No. 18/707,136 (the ‘136 Application) in view of Locke et al. 2020 (Blood Adv. 4 (19): 4898–4911), as applied to claims 3 and 4, respectively, and further in view of Newell and Holtan 2017 (Blood Reviews, 31; 57-62).
The combined teachings the claims in the ‘136 Application in view of Locke et al. pertaining to claims 3 and 4 and the rationale for combining them is outlined in the NSDP rejection above.
The combined reference teachings differ from the instant invention by not teaching that the one or more inflammation-related soluble factors is PGF.
The teachings of Newell and Holtan are outlined in the 103 rejection above.
It would be obvious to one of ordinary skill in the to modify the combined teachings of the claims in the ‘136 Application in view of Locke et al. as applied to claims 3 and 4, and to incorporate the teachings of Newell and Holtan to include that the one or more inflammation-related soluble factors is PGF.
Given that PGF appears to be a key regulatory factor involved in controlling inflammatory responses; it would have been obvious to a skilled artisan to experiment with using PGF as the one or more inflammation-related soluble factors measured to determine the inflammatory status of the patients in the method of selecting and treating multiple myeloma patients as taught by the claims in the ‘136 Application in view of Locke et al. with a reasonable expectation of success.
Combining prior art elements according to known methods to yield predictable results is obvious to one of ordinary skill in the art (see MPEP § 2143(A)). From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Therefore, the claims in the ‘136 Application would render the instant claims obvious.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
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/GRACE H LUNDE/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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