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 .
Detailed Action
This action is in response to the papers filed December 18, 2025.
Amendments
Applicant's response and amendments, filed December 18, 2025, to the prior Office Action is acknowledged. Applicant has cancelled Claims 2-8, 13-14, 18-21, 24-30, 32-34, 38, 40-44, and 46-55, amended Claim 12, withdrawn Claims 31, 35-37, and 45, and added new claim, Claim 57.
Claims 1, 9-12, 15-17, 22-23, 31, 35-37, 39, 45, and 56-57 are pending.
Election/Restrictions
Applicant has elected without traverse the invention of Group III, Claim(s) 1-3, 9-12, 15-17, 22-23, 31, 35-37, 39, 45, drawn to an in vitro or ex vivo method comprising:
(a) obtaining a sample of cells, the sample comprising CD161+ T cells; and
(b) culturing the T cells in the presence of IL-7, IL-15 and IL-21,
thereby providing a population of T-cells that are expanded in the number of CD161+ cells as compared to non-CD161+ cells.
Within Group III, Applicant has elected without traverse the following species, wherein:
i) alternative first order additional method step is culturing the CD8+ CD161+ T cells in the presence of IL-7, IL-15, IL-21, a CD3-binding antibody, a CD28-binding antibody, and Clec2d, as recited in Claims 9-10; and
ii) alternative second order additional method step is Claim 39, culturing in the presence of DCs or aAPCs.
Claims 1, 9-12, 15-17, 22-23, 31, 35-37, 39, 45, and 56-57 are pending.
Claims 16-17, 31, 35-37, 39, and 45 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 1, 9-12, 15, 22-23, and 56-57 are under consideration.
Priority
This application is a 371 of PCT/US2020/059344 filed on November 6, 2020. Applicant’s claim for the benefit of a prior-filed application provisional application 62/931,670, filed on November 6, 2019 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Information Disclosure Statement
Applicant has filed an Information Disclosure Statements on June 24, 2025 and December 29, 2025 that has been considered.
The signed and initialed PTO Forms 1449 are mailed with this action.
Specification
1. The prior objection to the disclosure is withdrawn in light of Applicant’s amendment to the specification to replace the phrases “anti-CD3/CD28/Clec2d” with “anti-CD3/CD28 and recombinant Clec2d”, which the Examiner finds persuasive.
Claim Rejections - 35 USC § 112
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.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
2. The prior rejection of Claim 12 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of Applicant’s amendment to the claim cancelling recitation of “about”, which the Examiner finds persuasive.
3. Claim 57 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 1 recites the step of culturing a population of CD8+, CD161+ T cells in the presence of IL-7, IL-15, IL-21, an anti-CD3 antibody, an anti-CD28 antibody, and Clec2 protein,
thereby providing a population of CD8+, CD161+ T cells that have upregulated granzyme and perforin expression as compared to CD8+, CD161+ T cells not cultured in the presence of IL-7, IL-15, IL-21, an anti-CD3 antibody, an anti-CD28 antibody, and Clec2 protein.
Claim 57, depending upon Claim 1, recites wherein the provided population of CD8+, CD161+ T cells have increased cytotoxic capacity as compared to CD8+, CD161+ T cells not cultured in the presence of IL-7, IL-15, IL-21, an anti-CD3 antibody, an anti-CD28 antibody, and Clec2 protein.
Either the functional property of Claim 57 is an inherent property of (that naturally flows from) the thus-provided population of CD8+, CD161+ T cells that have upregulated granzyme and perforin expression as compared to CD8+, CD161+ T cells of Claim 1, or it is not, and something of independent Claim 1 method step(s) must change.
To the extent it is an inherent property of (that naturally flows from) the method of the independent claim, then the instant claim fails to further limit the independent claim.
Furthermore, in regard to instant claims, it is noted that the “wherein the provided population of CD8+, CD161+ T cells have increased cytotoxic capacity” clause does not recite any additional structure(s) and/or active method step(s), but simply states a characterization or conclusion of the population of CD8+, CD161+ T cells that have upregulated granzyme and perforin expression positively recited in Claim 1. Therefore, the "wherein" clause is not considered to further limit the method defined by the claim and has not been given weight in construing the claims. See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171,26 USPQ2d 1018, 1023 (Fed Cir. 1993) ("A 'whereby' clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim."). See also Minton v. National Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003) ("A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.").
The specification fails to disclose a population of CD8+, CD161+ T cells that have upregulated granzyme and perforin expression (Claim 1), yet does NOT also have increased cytotoxic capacity (Claim 57).
'Even if such a phrase did hold patentable weight, the phrase would likely be rejected under 35 USC 112(b) for being indefinite because such a phrase would amount to a 'functional limitation' whereby one of ordinary skill in the art would essentially need to 'guess' what steps must occur in the claim, in addition to the positively-recited method steps, in order to result in 'wherein the....' (the 'intended result' phrase in the claim).
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
4. Claim(s) 57 is 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.
Claim 1 recites the step of culturing a population of CD8+, CD161+ T cells in the presence of IL-7, IL-15, IL-21, an anti-CD3 antibody, an anti-CD28 antibody, and Clec2 protein,
thereby providing a population of CD8+, CD161+ T cells that have upregulated granzyme and perforin expression as compared to CD8+, CD161+ T cells not cultured in the presence of IL-7, IL-15, IL-21, an anti-CD3 antibody, an anti-CD28 antibody, and Clec2 protein.
Claim 57, depending upon Claim 1, recites wherein the provided population of CD8+, CD161+ T cells have increased cytotoxic capacity as compared to CD8+, CD161+ T cells not cultured in the presence of IL-7, IL-15, IL-21, an anti-CD3 antibody, an anti-CD28 antibody, and Clec2 protein.
Either the functional property of Claim 57 is an inherent property of (that naturally flows from) the thus-provided population of CD8+, CD161+ T cells that have upregulated granzyme and perforin expression as compared to CD8+, CD161+ T cells of Claim 1, or it is not, and something of independent Claim 1 method step(s) must change.
The claim denotes that not all of the populations of CD8+, CD161+ T cells that have upregulated granzyme and perforin expression of the independent claim are able to achieve the functional property(ies) having increased cytotoxic capacity recited in the dependent claim(s).
To the extent it is not an inherent property (that naturally flows) from the method of the independent claim, then something must change. The claim is considered to lack adequate written description for failing to recite the structure(s) and/or method step(s) that is/are necessary and sufficient to cause the recited functional language in the dependent claim.
The limitation “wherein the provided population of CD8+, CD161+ T cells have increased cytotoxic capacity” merely states a functional characteristic without providing any indication about how the functional characteristic is provided. The functional characteristic does not follow from (is not an inherent property of) the structure/method step(s) recited in the independent claim, and thus the ordinary artisan would not know what modification(s) must be made in order to fulfill the instant recitation.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
The claims fail to recite, and the specification fails to disclose, a first method step of culturing a population of CD8+, CD161+ T cells in the presence of IL-7, IL-15, IL-21, an anti-CD3 antibody, an anti-CD28 antibody, and Clec2 protein,
thereby providing a population of CD8+, CD161+ T cells that have upregulated granzyme and perforin expression as compared to CD8+, CD161+ T cells not cultured in the presence of IL-7, IL-15, IL-21, an anti-CD3 antibody, an anti-CD28 antibody, and Clec2 protein (Claim 1),
wherein said population of CD8+, CD161+ T cells that have upregulated granzyme and perforin expression do not also have the functional property of increased cytotoxic capacity as compared to CD8+, CD161+ T cells not cultured in the presence of IL-7, IL-15, IL-21, an anti-CD3 antibody, an anti-CD28 antibody, and Clec2 protein (Claim 57), as opposed to a second method step of culturing a population of CD8+, CD161+ T cells in the presence of IL-7, IL-15, IL-21, an anti-CD3 antibody, an anti-CD28 antibody, and Clec2 protein,
thereby providing a population of CD8+, CD161+ T cells that have upregulated granzyme and perforin expression as compared to CD8+, CD161+ T cells not cultured in the presence of IL-7, IL-15, IL-21, an anti-CD3 antibody, an anti-CD28 antibody, and Clec2 protein (Claim 1),
wherein said population of CD8+, CD161+ T cells that have upregulated granzyme and perforin expression necessarily and predictably have the functional property of increased cytotoxic capacity as compared to CD8+, CD161+ T cells not cultured in the presence of IL-7, IL-15, IL-21, an anti-CD3 antibody, an anti-CD28 antibody, and Clec2 protein (Claim 57), for example.
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
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 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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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.
5. Claims 1, 15, 22-23, and 56-57 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Kwoczek et al (available online October 11, 2017; of record) in view of Takahashi et al (2006; of record in IDS), Exley et al (1998; of record), Rother et al (available online August 26, 2015; of record), Temme (WO 20/104676; priority to November 23, 2018; of record), and Wittrup et al (U.S. 2021/0122826; priority to October 24, 2019; of record).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
With respect to Claim 1, Kwoczek et al is considered relevant prior art for having taught a method for culturing a CD8+ T cell population in vitro, the method comprising the step(s) of:
(a) obtaining a sample of cells from a subject, the sample comprising T cells (e.g. pg 89, col. 2, Methods, Cord Blood and Peripheral Blood samples); and
(b) culturing the sample comprising T cells in the presence of:
i) IL-2, IL-7, IL-15, and IL-21; and
ii) anti-CD3/anti-CD28 antibodies (e.g pg 89, col. 2, Methods, Polyclonal T-cell activation).
Kwoczek et al taught wherein the IL-7/15/21 combination enhances expansion of antigen-specific CD8+ T cells from the cord and peripheral blood samples, as compared to IL-7/15 combination (e.g. Figure 4c), reduced IFNgamma production (e.g. Figure 6c), and increased granzyme B production (e.g. Figure 6d).
Thus, prior to the effective filing date of the instantly claimed invention, those of ordinary skill in the art previously recognized the scientific and technical concepts of using the combination of IL-2, -7, -15, and -21, anti-CD3 antibodies, and anti-CD28 antibodies, to stimulate CD8+ CD161+ T cells.
Takahashi et al is considered relevant prior art for having taught a method for culturing T cell population in vitro, the method comprising the step(s) of:
(a) obtaining a sample of cells from a subject, the sample comprising T cells (e.g. pg 211, col. 2, Methods, “Peripheral blood was obtained from healthy donors”); and
(b) culturing the sample comprising T cells in the presence of:
i) IL-2; and
ii) anti-CD3/anti-CD28 antibodies (e.g pg 212, col. 1, Methods, Proliferation assays).
Takahashi et al taught wherein the PBMCs inherently and naturally comprise CD8+ CD161+ T cells (e.g. pg 212, col. 2, Results; Figure 1).
Takahashi et al taught wherein the CD8+ CD161+ T cells inherently and naturally produce higher amounts of granzyme A and perforin, as compared to CD8+ CD161- T cells (e.g. Figure 7).
Neither Kwoczek et al nor Takahashi et al teach wherein the culturing method comprises the use of CLEC2D.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim(s) 1, Exley et al is considered relevant prior art for having taught a method of culturing CD161+ T cells in vitro, the method comprising the step(s) of:
(a) obtaining a sample of CD161+ T cells from a subject (e.g. pg 868, col. 1, Methods, “human peripheral blood”); and
(b) culturing the sample comprising CD161+T cells in the presence of:
i) IL-2;
ii) anti-CD3 antibodies (e.g pg 868, col. 2, Methods; pg 869, col. 2); and
iii) anti-CD161 antibodies (pg 868, col. 2, Antibodies DX-1 and 191.B8).
Exley et al taught that anti-CD161 antibodies DX-1 and 191.B8 are agonistic, substantially augmenting proliferation of anti-CD3 stimulated T cells (e.g. pg 869, col. 2; Table 1; Figure 2E).
Thus, prior to the effective filing date of the instantly claimed invention, those of ordinary skill in the art previously recognized the scientific and technical concepts of using the combination of IL-2, anti-CD3 antibodies, and a CD161 agonist, e.g. an anti-CD161 antibody to stimulate CD161+ T cells.
Rother et al is considered relevant prior art for having taught a method of culturing CD161+ T cells in vitro, the method comprising the step(s) of:
(a) obtaining a sample of CD161+ T cells from a subject (e.g. pg 2, Methods, human, whole blood donors; pg 3, Human primary cells (PBMC)); and
(b) culturing the sample comprising CD161+ T cells in the presence of:
iii) anti-CD161 agonistic antibodies or recombinant CLEC2D (e.g. Abstract; pg 7, soluble LLT1 (syn. CLEC2D)-Fc; pg 5, PBMC were stimulated with…anti-CD161 mAb 191.B8).
Thus, prior to the effective filing date of the instantly claimed invention, those of ordinary skill in the art previously recognized the scientific and technical concepts of substituting a first CD161 agonist, e.g. an anti-CD161 antibody, with a second agonist, e.g. recombinant CLEC2D, to stimulate CD161+ T cells.
Temme is considered relevant prior art for having disclosed a method of culturing CD161+ immune cells, the method comprising the step(s) of:
(a) obtaining a sample of CD161+ immune cells from a subject (e.g. pg 25, lines 25-26, isolated from peripheral blood; pg 42, line 13); and
(b) culturing the sample comprising CD161+ immune cells in the presence of:
i) IL-15 and/or IL-21; and
iii) LLT1 (syn. CLEC2D; e.g. pgs 22-23, joining para; pg 24, lines 14-25),
thereby inducing proliferation and/or expansion of the CD161+ immune cells.
Temme disclosed that IL-15 and IL-21 were already known in the art to promote NK cell expansion (e.g. pg 21, lines 8-9), and induces proliferation of T and NK cells, as well as inducing CD8+ memory T cells (e.g. pg 27, lines 24-27).
Thus, prior to the effective filing date of the instantly claimed invention, those of ordinary skill in the art previously recognized the scientific and technical concepts of culturing CD161+ immune cells in the presence of a combination of IL-15, IL-21, and CLEC2D.
Wittrup et al is considered relevant prior art for having disclosed a method of culturing CD161+ immune cells, the method comprising the step(s) of:
(a) obtaining a sample of CD161+ immune cells, e.g. T or NK cells [0303], from a subject (e.g. [1328], CD161-expressing T cells…isolated from peripheral blood, primary human T cells); and
(b) culturing the sample comprising CD161+ immune cells in the presence of:
iii) an agonistic antibody that binds CD161 and is effective for blocking or inhibiting the binding of CLEC2D to CD161 (e.g. [0007, 1120-1121]),
wherein said antibody may induce, promoter, or enhance immune cell activation, proliferation, or cytolytic function of CD161-expressing immune cells, e.g. T or NK cells [0365-366], e.g. CD8+ T cells [1304].
Wittrup et al disclosed that blocking the CLEC2D-CD161 interaction with the agonistic anti-CD161 antibody yields a reduced exhaustion response [0347], whereby hallmarks of T cell exhaustion include poor responsiveness to IL-7 and IL-15, and decreased proliferative capacity [1109].
As discussed above, Rother et al taught that anti-CD161 mAb 191.B8 (as per Exley et al) blocks binding of LLT1 to CD161 (pg 9).
As discussed above, Exley et al taught that anti-CD161 mAb 191.B8 is agonistic, substantially augmenting proliferation of anti-CD3 stimulated T cells (e.g. pg 869, col. 2; Table 1; Figure 2E).
Wittrup et al disclosed that methods of inducing activation of isolated T cells are known in the art, and include the use of anti-CD3 and anti-CD28 antibodies (e.g. [1303]).
Wittrup et al disclosed the use of recombinant CLEC2D protein to bind CD161 on T cells (e.g. [0334]).
Resolving the level of ordinary skill in the pertinent art.
People of the ordinary skill in the art will be highly educated individuals such as medical doctors, scientists, or engineers possessing advanced degrees, including M.D.'s and Ph.D.'s. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in immunology and the culturing and expansion of primary immune cells, including T cells. Therefore, the level of ordinary skill in this art is high.
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at ___, 82 USPQ2d at 1396.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to modify a method of culturing a CD8+ CD161+ T cell population in vitro, the method comprising the step(s) of:
(a) obtaining a sample of CD8+ CD161+ T cells from a subject; and
(b) culturing the sample comprising T cells in the presence of:
i) IL-2, IL-7, IL-15, and IL-21; and
ii) anti-CD3/anti-CD28 antibodies,
to further comprise the
(b) culturing the sample comprising T cells in the presence of CLEC2D,
with a reasonable expectation of success because those of ordinary skill in the art previously recognized the scientific and technical concepts of:
i) culturing CD161+ immune cells in the presence of a combination of IL-2, -7, -15, and -21, anti-CD3 antibodies, and anti-CD28 antibodies, to stimulate CD8+ CD161+ T cells (Kwoczek et al), whereby methods of inducing activation of isolated T cells are known in the art, and include the use of anti-CD3 and anti-CD28 antibodies (e.g. Wittrup et al, [1303]);
ii) culturing CD161+ immune cells in the presence of a combination of IL-2, anti-CD3 antibodies, and a CD161 agonist, e.g. an anti-CD161 antibody to stimulate CD161+ T cells (Exley et al);
iii) culturing CD161+ immune cells in the presence of a combination of IL-15, IL-21, and CLEC2D (Temme); and
iv) substituting a first CD161 agonist, e.g. an anti-CD161 antibody, with a second agonist, e.g. recombinant CLEC2D, to stimulate CD161+ T cells (Rother et al; Wittrup et al, [0334]).
One of ordinary skill in the art would have been motivated to make such a modification because Wittrup et al disclosed that blocking the CLEC2D-CD161 interaction with the anti-CD161 antibody may induce, promoter, or enhance immune cell activation, proliferation, or cytolytic function of CD161-expressing immune cells, e.g. T or NK cells, including CD8+ T cells, and yields a reduced exhaustion response, whereby hallmarks of T cell exhaustion include poor responsiveness to IL-7 and IL-15, and decreased proliferative capacity.
As discussed above, Exley et al taught that anti-CD161 mAb 191.B8 is agonistic, substantially augmenting proliferation of anti-CD3 stimulated T cells.
The motivation to combine can arise from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combined for their common known purpose. MPEP §2144.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claims 15 and 56, Kwoczek et al taught wherein:
IL-7 is present at about 10 ng/ml,
IL-15 is present at about 10 ng/ml, and
IL-21 is present at about 10 ng/ml (e.g. pg 89, col. 2, Methods, Polyclonal T-cell activation).
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
Independent Claim 1 is recited at a high level of generality. Instant specification fails to disclose an element of criticality for the presently recited concentrations, individually and/or in combination and/or subcombination thereof.
With respect to Claims 22-23, Kwoczek et al taught wherein the sample of T cells are obtained from a subject (e.g. pg 89, col. 2, Methods, Cord Blood and Peripheral Blood samples).
Takahashi et al taught wherein the sample of T cells comprising CD8+ CD161+ T cells are obtained from a subject (e.g. pg 211, col. 2, Methods, Peripheral Blood).
Exley et al taught wherein the sample of T cells comprising CD161+ T cells are obtained from a subject (e.g. pg 868, col. 1, Methods, human peripheral blood).
Rother et al taught wherein the sample of T cells comprising CD161+ T cells are obtained from a subject (e.g. pg 2, Methods; pg 3, Human peripheral blood).
Temme disclosed the sample of CD161+ immune cells are obtained from a subject (e.g. pg 25, lines 25-26).
Wittrup et al disclosed the sample of CD161+ immune cells are obtained from a subject (e.g. [1303, 1328]).
With respect to Claim 57, as discussed above per the 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, the claim fails to further limit the independent claim.
To the extent Applicant argues otherwise, then see above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description rejection.
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Response to Arguments
Applicant argues that Kwoczek et al is not directed to a method for generating CD8+ CD161+ T cells with upregulated granzyme and perforin expression.
Applicant’s argument(s) has been fully considered, but is not persuasive. The Examiner must determine what is "analogous prior art" for the purpose of analyzing the obviousness of the subject matter at issue. **>"Under the correct analysis, any need or problem known in the field of endeavor at the time of the invention and addressed by the patent [or application at issue] can provide a reason for combining the elements in the manner claimed. " KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1397 (2007). Thus a reference in a field different from that of applicant's endeavor may be reasonably pertinent if it is one which, because of the matter with which it deals, logically would have commended itself to an inventor's attention in considering his or her invention as a whole.<
Kwoczek et al is considered relevant prior art for having taught a method for culturing a CD8+ T cell population in vitro, the method comprising the step(s) of:
(a) obtaining a sample of cells from a subject, the sample comprising T cells (e.g. pg 89, col. 2, Methods, Cord Blood and Peripheral Blood samples); and
(b) culturing the sample comprising T cells in the presence of:
i) IL-2, IL-7, IL-15, and IL-21; and
ii) anti-CD3/anti-CD28 antibodies (e.g pg 89, col. 2, Methods, Polyclonal T-cell activation).
Kwoczek et al taught wherein the IL-7/15/21 combination enhances expansion of antigen-specific CD8+ T cells from the cord and peripheral blood samples, as compared to IL-7/15 combination (e.g. Figure 4c), reduced IFNgamma production (e.g. Figure 6c), and increased granzyme B production (e.g. Figure 6d).
Thus, prior to the effective filing date of the instantly claimed invention, those of ordinary skill in the art previously recognized the scientific and technical concepts of using the combination of IL-2, -7, -15, and -21, anti-CD3 antibodies, and anti-CD28 antibodies, to stimulate CD8+ CD161+ T cells.
It is axiomatic that the population of CD8+ T cells isolated by Kwoczek et al from cord and peripheral blood inherently and naturally comprise CD8+, CD161+ T cells per natural laws of cell biology, anatomy, and physiology, as evidenced by Takahashi et al (pgs 211-212, Methods, isolation of CD8+ CD161+ T cells from peripheral blood).
Kwoczek et al taught that the CD8+ T cells incubated with IL-7, -15, and -21 produced greater amounts of granzyme B than CD8+ T cells not incubated with IL-7, -15, and -21 (e.g. Figure 6D).
Applicant argues that Takahashi et al teach away from the claimed invention because Takahashi et al taught the CD8+, CD161+ T cells were anergic, exhibiting minimal cytokine secretion, failed to proliferate, and lacked cytotoxic function.
Applicant’s argument(s) has been fully considered, but is not persuasive. Independent Claim 1 does not require proliferation, exhibiting some arbitrary and subjective amount of cytokine secretion, lack of anergy, and/or cytotoxic function. All that is required is a culturing step, which is what Takahashi et al reduced to practice.
Takahashi et al is silent to culturing the CD8+, CD161+ T cells with IL-7, -15, and -21, let alone Clec2d. Such silence is not considered to teach away from the instantly claimed invention because it does not discredit or otherwise discourage the ordinary artisan from culturing the CD8+, CD161+ T cells with IL-7, -15, and -21, let alone Clec2d.
Applicant argues that while Takahashi et al taught intracellular staining for granzyme and perforin, this does not equate to functional secretion of these molecules.
Applicant’s argument(s) has been fully considered, but is not persuasive. Independent Claim 1 does not require functional secretion of granzyme and perforin. Rather, all that the claim requires is upregulated granzyme and perforin expression. Takahashi et al taught the relative amounts of granzyme and perforin expression is greater, up to 88% and 93%, respectively, in CD8+, CD161+ T cells, relative to CD8+, CD161- T cells (e.g. Figure 7). Furthermore, Takahashi et al taught that increased intracellular cytolytic granules, including perforin and granzyme A, contribute to the spontaneous cytolytic activity of the NK cells (e.g. pg 214, col. 2), and that the CD8+ CD161+ T cells were able to lyse (syn. cytolytic activity) target cells (e.g. pg 215, col. 2).
Applicant argues that Takahashi et al do not teach a deliberate effort to define a specialized cytokine environment aimed at promoting the functional enhancement of an already defined CD8+, CD161+ T cell subset.
Applicant’s argument(s) has been fully considered, but is not persuasive. The Examiner must determine what is "analogous prior art" for the purpose of analyzing the obviousness of the subject matter at issue. **>"Under the correct analysis, any need or problem known in the field of endeavor at the time of the invention and addressed by the patent [or application at issue] can provide a reason for combining the elements in the manner claimed. " KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1397 (2007). Thus a reference in a field different from that of applicant's endeavor may be reasonably pertinent if it is one which, because of the matter with which it deals, logically would have commended itself to an inventor's attention in considering his or her invention as a whole.<
Takahashi et al taught wherein the CD8+ CD161+ T cells inherently and naturally produce higher amounts of granzyme A and perforin, as compared to CD8+ CD161- T cells (e.g. Figure 7).
Applicant argues that both Exley et al and Rother et al focus on CD161 function in the context of NK cells, not CD8+, CD161+ T cells.
Applicant’s argument(s) has been fully considered, but is not persuasive. The Examiner must determine what is "analogous prior art" for the purpose of analyzing the obviousness of the subject matter at issue. **>"Under the correct analysis, any need or problem known in the field of endeavor at the time of the invention and addressed by the patent [or application at issue] can provide a reason for combining the elements in the manner claimed. " KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1397 (2007). Thus a reference in a field different from that of applicant's endeavor may be reasonably pertinent if it is one which, because of the matter with which it deals, logically would have commended itself to an inventor's attention in considering his or her invention as a whole.<
Exley et al is considered relevant prior art for having taught a method of culturing CD161+ T cells in vitro, the method comprising the step(s) of:
(a) obtaining a sample of CD161+ T cells from a subject (e.g. pg 868, col. 1, Methods, “human peripheral blood”); and
(b) culturing the sample comprising CD161+T cells in the presence of:
i) IL-2;
ii) anti-CD3 antibodies (e.g pg 868, col. 2, Methods; pg 869, col. 2); and
iii) anti-CD161 antibodies (pg 868, col. 2, Antibodies DX-1 and 191.B8).
Exley et al taught that anti-CD161 antibodies DX-1 and 191.B8 are agonistic, substantially augmenting proliferation of anti-CD3 stimulated T cells (e.g. pg 869, col. 2; Table 1; Figure 2E).
Exley et al taught that CD161-ligand interactions positively regulate CD161+ T cell activation of antigen-specific TCRs (e.g. pg 873, col. 1).
Thus, prior to the effective filing date of the instantly claimed invention, those of ordinary skill in the art previously recognized the scientific and technical concepts of using the combination of IL-2, anti-CD3 antibodies, and a CD161 agonist, e.g. an anti-CD161 antibody to stimulate CD161+ T cells.
Rother et al is considered relevant prior art for having taught a method of culturing CD161+ T cells in vitro, the method comprising the step(s) of:
(a) obtaining a sample of CD161+ T cells from a subject (e.g. pg 2, Methods, human, whole blood donors; pg 3, Human primary cells (PBMC)); and
(b) culturing the sample comprising CD161+ T cells in the presence of:
iii) anti-CD161 agonistic antibodies or recombinant CLEC2D (e.g. Abstract; pg 7, soluble LLT1 (syn. CLEC2D)-Fc; pg 5, PBMC were stimulated with…anti-CD161 mAb 191.B8).
Thus, prior to the effective filing date of the instantly claimed invention, those of ordinary skill in the art previously recognized the scientific and technical concepts of substituting a first CD161 agonist, e.g. an anti-CD161 antibody, with a second agonist, e.g. recombinant CLEC2D, to stimulate CD161+ T cells.
Furthermore, the Examiner provides the following references to rebut applicant’s arguments regarding the state of the prior art between NK cell and T cell responses to CD161. Note: these references are not considered a part of the 103 rejection but are solely provided to rebut applicant’s argument(s).
Rother et al cite (pg 2, citation #18) Germain et al (Induction of Lectin-like Transcript 1 (LLT1) Protein Cell Surface Expression by Pathogens and Interferon-gamma Contributes to Modulate Immune Responses, J. Biol. Chem. 286(44): 37964-37975, 2011) who taught that while the LTT1 (syn. Clec2D)/CD161 interaction inhibits NK cells, it co-stimulates T cells (e.g. pg 37969, col. 2 “the LLT1/CD161 interaction on one hand inhibits NK cell activation and on the other hand costimulates T cells”).
See also Braud et al (U.S. 2009/0074756) who disclosed “as opposed to NK cells, LLTl interaction with CD161 expressed by T cells triggers a costimulatory signal resulting in an increase of IFN-y production triggered by CD3 ligation” (e.g. Example 7, [0202]).
Thus, prior to the effective filing date of the instantly claimed invention, at least a decade, those of ordinary skill in the art previously recognized the scientific and technical concepts that CD161+ T cells respond differently to the CD161 ligand Clec2D (syn. LTT1) than NK cells.
Applicant argues that Temme is concerned with the expansion of NK cells, not CD8+, CD161+ T cells.
Applicant’s argument(s) has been fully considered, but is not persuasive. The Examiner must determine what is "analogous prior art" for the purpose of analyzing the obviousness of the subject matter at issue. **>"Under the correct analysis, any need or problem known in the field of endeavor at the time of the invention and addressed by the patent [or application at issue] can provide a reason for combining the elements in the manner claimed. " KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1397 (2007). Thus a reference in a field different from that of applicant's endeavor may be reasonably pertinent if it is one which, because of the matter with which it deals, logically would have commended itself to an inventor's attention in considering his or her invention as a whole.<
Temme is considered relevant prior art for having disclosed a method of culturing CD161+ immune cells, the method comprising the step(s) of:
(a) obtaining a sample of CD161+ immune cells from a subject (e.g. pg 25, lines 25-26, isolated from peripheral blood; pg 42, line 13); and
(b) culturing the sample comprising CD161+ immune cells in the presence of:
i) IL-15 and/or IL-21; and
iii) LLT1 (syn. CLEC2D; e.g. pgs 22-23, joining para; pg 24, lines 14-25),
thereby inducing proliferation and/or expansion of the CD161+ immune cells.
Temme disclosed that IL-15 and IL-21 were already known in the art to promote NK cell expansion (e.g. pg 21, lines 8-9), and induces proliferation of T and NK cells, as well as inducing CD8+ memory T cells (e.g. pg 27, lines 24-27).
Thus, prior to the effective filing date of the instantly claimed invention, those of ordinary skill in the art previously recognized the scientific and technical concepts of culturing CD161+ immune cells in the presence of a combination of IL-15, IL-21, and CLEC2D.
Applicant argues that Temme does not disclose CD8+, CD161+ T cells.
Applicant’s argument(s) has been fully considered, but is not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Takahashi et al and Rother et al taught CD8+ CD161+ T cells.
Applicant argues that Wittrup et al teach away from the claimed invention because Wittrup et al disclose monoclonal antibodies designed to block the interaction between CD161 (KLRB1) and its ligand Clec2d (LLTl) in order to relieve CD161-mediated immune suppression. Wittrup et al disclose the premise that Clec2d engagement of CD161 is inhibitory, and therefore, blocking it would enhance T cell function. This view directly contradicts the approach of the present invention, which includes Clec2d as a key stimulatory component in the culture environment to enhance granzyme and perforin expression in CD8+ CD161+ T cells.
Applicant’s argument(s) has been fully considered, but is not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
While Wittrup et al disclosed the anti-CD161 antibodies are able to block the interaction between Clec2D and CD161, said antibodies are also recognized to be co-stimulatory for T cells. Wittrup et al do not disclose or teach away that recombinant Clec2D does not elicit T cell activation as do agonistic anti-CD161 antibodies.
Exley et al taught the anti-CD161 antibodies, e.g. HP-3G10 (e.g. pg 871, col. 2, also used by Wittrup et al) are agonistic, substantially augmenting proliferation of anti-CD3 stimulated T cells (e.g. pg 869, col. 2; Table 1; Figure 2E).
Rother et al taught that recombinant Clec2D (syn. soluble LLT1-Fc) acts upon CD161 in the same direction as agonistic anti-CD161 antibodies (e.g. pg 2, “Triggering of CD161 by binding of LTT1 or agonistic antibodies”).
And, as discussed above, those of ordinary skill in the art previously recognized, by at least a decade before the effective filing date of the instantly claimed invention, the scientific and technical concepts that CD161+ T cells respond differently to the CD161 ligand Clec2D (syn. LTT1) than NK cells (as per Rother et al’s citation of Germain et al, and Braud et al).
6. Claims 9-12, 15, 22-23, and 56-57 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Kwoczek et al (available online October 11, 2017; of record) in view of Takahashi et al (2006; of record in IDS), Exley et al (1998; of record), Rother et al (available online August 26, 2015; of record), Temme (WO 20/104676; priority to November 23, 2018; of record), and Wittrup et al (U.S. 2021/0122826; priority to October 24, 2019; of record), as applied to Claims 1, 15, 22-23, and 56 above, and in further view of Zoon et al (2015; of record in IDS).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Wittrup et al disclosed an example of culturing primary CD161+ T cells, the method comprising the step(s) of:
a) obtaining a sample of CD161+ T cells from peripheral human blood; and
b) culturing the T cells in the presence of:
i) IL-2; and
ii) anti-CD3 and anti-CD28 antibodies (e.g. Example 4, [1328]),
wherein the method further comprises the step(s) of:
c) culturing the CD161+ T cells:
i) in the presence of IL-2; and
ii) in the absence of anti-CD3 and anti-CD28 antibodies, to thereby rest the T cells (e.g. Example 12, [1375]).
Similarly, Zoon et al is considered relevant prior art for having taught a method for expanding a CD8+ T cell population in vitro, the method comprising the step(s) of:
(a) obtaining a sample of cells, the sample comprising T cells (e.g. pg 8755, Methods, 4.4, draining lymph nodes or spleen); and
(b) culturing the T cells in the presence of IL-7, IL-15, and IL-21 (e.g. pg 8755, Methods, 4.4).
Zoon et al taught wherein the method further comprises a step (c) of culturing the CD8+ T cells:
i) in the presence of IL-7, IL-15, and IL-21; and
ii) without antibody stimulation (e.g. the culture is split every 2-3 days (syn. 24-72 hours), culturing to as many as 6-7 days, to maintain the cells (e.g. pg 8755, Methods, 4.4).
Zoon et al taught the combination of IL-7/15/21 induced greater expansion of lymphocytes in culture, as compared to IL-2, increased the yield of CD8+ central memory T cells, whereby the expanded T cell population was more effective at reducing tumor metastases, such advantages may have significant impact on future clinical trials of adoptive immunotherapy, particularly for generating adequate numbers of lymphocytes for treatment (e.g. Abstract).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to modify a method of culturing a CD8+ CD161+ T cell population in vitro to further comprise a step of culturing said T cells in the absence of anti-CD3 and anti-CD28 antibodies with a reasonable expectation of success because those of ordinary skill in the art previously recognized the scientific and technical concepts of culturing previously stimulated T cells in the absence of anti-CD3 and anti-CD28 antibodies for a period of time, e.g. 72 hours, so as to rest the T cells prior to subsequent activation experiments (Wittrup et al, Zoon et al).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claims 15 and 56, Kwoczek et al taught wherein:
IL-7 is present at about 10 ng/ml,
IL-15 is present at about 10 ng/ml, and
IL-21 is present at about 10 ng/ml (e.g. pg 89, col. 2, Methods, Polyclonal T-cell activation).
Zoon et al taught wherein:
IL-7 is present at about 5 ng/ml,
IL-15 is present at about 5 ng/ml, and
IL-21 is present at about 5 ng/ml (e.g. pg 8755, Methods, 4.4).
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
Independent Claim 1 is recited at a high level of generality. Instant specification fails to disclose an element of criticality for the presently recited concentrations, individually and/or in combination and/or subcombination thereof.
With respect to Claims 22-23, Kwoczek et al taught wherein the sample of T cells are obtained from a subject (e.g. pg 89, col. 2, Methods, Cord Blood and Peripheral Blood samples).
Takahashi et al taught wherein the sample of T cells comprising CD8+ CD161+ T cells are obtained from a subject (e.g. pg 211, col. 2, Methods, Peripheral Blood).
Exley et al taught wherein the sample of T cells comprising CD161+ T cells are obtained from a subject (e.g. pg 868, col. 1, Methods, human peripheral blood).
Rother et al taught wherein the sample of T cells comprising CD161+ T cells are obtained from a subject (e.g. pg 2, Methods; pg 3, Human peripheral blood).
Temme disclosed the sample of CD161+ immune cells are obtained from a subject (e.g. pg 25, lines 25-26).
Wittrup et al disclosed the sample of CD161+ immune cells are obtained from a subject (e.g. [1303, 1328]).
Zoon et al taught wherein the sample of T cells are obtained from a subject (e.g. pg 8755, Methods, 4.4, draining lymph nodes or spleen).
With respect to Claim 10, Wittrup et al do not disclose the use of anti-CD161 antibodies or CLEC2D when culturing the CD161+ T cells in the absence of anti-CD3 and anti-CD28 antibodies.
Zoon et al do not teach the use of anti-CD161 antibodies or CLEC2D when culturing the CD161+ T cells in the absence of anti-CD3 and anti-CD28 antibodies.
With respect to Claim 12, Wittrup et al disclosed wherein the culturing step in the absence of anti-CD3 and anti-CD28 antibodies is for about 72 hours (syn. 3 days) [1375].
Zoon et al taught wherein the culturing step without antibody stimulation is for about 48-72 hours (e.g. pg 8755, Methods, 4.4, the culture is split every 2-3 days (syn. 48-72 hours), culturing to as many as 6-7 days, to maintain the cells.
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
With respect to Claim 11, Kwoczek et al taught wherein the culturing of step (b) is for 7 days (e.g. pg 89, col. 2, Methods, Polyclonal T-cell activation).
Takahashi et al taught wherein the culturing of step (b) is for 3 days (syn. 72 hours) (e.g. pg 212, col. 1, Methods, Proliferation assays).
Exley et al taught wherein the culturing of step (b) is for 3 days (syn. 72 hours) (e.g. Figure 2, legend).
Wittrup et al disclosed wherein the culturing of step (b) is for 3 days (syn. 72 hours) (e.g. Example 4, [1328]).
Zoon et al taught wherein the culturing of step(b) is split every 2-3 days (syn. 24-72 hours) to maintain the cells (e.g. pg 8755, Methods, 4.4).
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
Independent Claim 1 is recited at a high level of generality. Instant specification fails to disclose an element of criticality for the presently recited cell culture temporal parameter range.
With respect to Claim 57, as discussed above per the 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, the claim fails to further limit the independent claim.
To the extent Applicant argues otherwise, then see above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description rejection.
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Response to Arguments
Applicant argues that Zoon et al do not cure the defect of Kwoczek et al in view of Takahashi et al, Exley et al, Rother et al, Temme, and Wittrup et al.
Applicant’s argument(s) has been fully considered, but is not persuasive. The Examiner’s response to Applicant's argument(s) regarding Kwoczek et al in view of Takahashi et al, Exley et al, Rother et al, Temme, and Wittrup et al are discussed above and incorporated herein.
Applicant does not contest the teachings of Zoon et al as applied to the obviousness to modify a method of culturing a CD8+ CD161+ T cell population in vitro to further comprise a step of culturing said T cells in the absence of anti-CD3 and anti-CD28 antibodies with a reasonable expectation of success because those of ordinary skill in the art previously recognized the scientific and technical concepts of culturing previously stimulated T cells in the absence of anti-CD3 and anti-CD28 antibodies for a period of time, e.g. 72 hours, so as to rest the T cells prior to subsequent activation experiments (Wittrup et al, Zoon et al).
Conclusion
7. No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638