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 September 15, 2025.
Amendments
Applicant's response and amendments, filed September 15, 2025, to the prior Office Action is acknowledged. Applicant has cancelled Claims 2-5, amended Claim 1 and 14-15, and withdrawn Claims 6-21, and added new claims, Claims 16-21.
Claims 1 and 6-21 are pending.
Election/Restrictions
Applicant has elected without traverse the invention of Group I, claim(s) 1-5, drawn to a method for preparation of an alpha/beta T processed cell, comprising the steps of:
i) in-vitro culturing an isolated peripheral blood mononuclear cell in the presence of
(1) IL-2,
(2) an anti-CD3 antibody, and
(3) 2-deoxy-d-glucose (2DG) or a derivative thereof.
Within Group I, Applicant has elected the following species, wherein:
i) the alternative cellular composition is alpha/beta T cells are contained at a proportion of around 74% to 90% and gamma/delta T cells and NK cells are contained at a proportion of around 10% to 26%, in said alpha/beta T processed cells, as recited in Claim 2; and
ii) the alternative 2-deoxyglucose compound is 2-DG itself, as recited in Claim 1.
Newly submitted Claims 16-21 are directed to an invention that is independent or distinct from the invention originally claimed for the following reasons: the claims are directed to methods of using cells to treat cancer or infection; whereas, the elected invention is directed to a method of making cells. While the method of use claims recite “produced according to the method of claim 1”, thus indicating a shared technical feature, as discussed below, this is not a special technical feature that contributes over the prior art. Rather, the special technical feature of Claims 16-21 is the step of administering the cell composition to a subject to treat disease.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, Claims 16-21 are withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Claims 1 and 6-21 are pending.
Claims 6-21 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.
Claim 1 is under consideration.
Priority
This application, filed August 6, 2020, is a 371 of PCT/JP2019/004357 filed on February 7, 2019.
Acknowledgment is made of Applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d) to PCT/JP2019/004357 filed on February 7, 2019, Japan 2018-184167 filed on September 28, 2018 and Japan 2018022488 filed on February 9, 2018.
While a certified copy of the foreign patent applications PCT/JP2019/004357 (syn. WO 19/156145), Japan 2018-184167, and Japan 2018022488 are provided with the instant application.
In the response filed June 7, 2024, Applicant has provided certified English translations of the JP 2018-184167 filed September 28, 2018 and JP 2018-022488 filed February 9, 2018.
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994)
The disclosure of the prior-filed application, Application No. JP 2018-022488 filed February 9, 2018, and JP 2018-184167 filed September 28, 2018 fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
Applicant has amended Claim 1 to recite the step(s) of culturing the PBMCs in vitro for a period of 1-2 weeks in the presence of:
i) IL-2 at a concentration of 175 to 2000 U/ml;
ii) anti-CD3 antibodies; and
iii) 2-DG at a concentration of 0.5 to 5mM.
JP 2018-022488 filed February 9, 2018 is silent to IL-2 at a concentration of 175 to 2000 U/ml, let alone 2-DG at a concentration of 0.5 to 5mM, now claimed.
At best, JP 2018-022488 filed February 9, 2018 discloses the combined parameters of culturing the PBMCs in vitro for a period of 1-2 weeks in the presence of:
i) IL-2 at a concentration of 175 U/ml;
ii) anti-CD3 antibodies; and
iii) 2-DG at a concentration of 2mM (e.g. pg 13, Example 1, certified English translation).
JP 2018-184167 filed September 28, 2018 suffers the same deficiencies.
At best, JP 2018-184167 filed September 28, 2018 discloses the combined parameters of culturing the PBMCs in vitro for a period of 1-2 weeks in the presence of:
i) IL-2 at a concentration of 175 U/ml;
ii) anti-CD3 antibodies; and
iii) 2-DG at a concentration of 2mM (e.g. pg 14, Example 1, certified English translation).
PCT/JP2019/004357 filed on February 7, 2019 suffers the same deficiencies.
At best, PCT/JP2019/004357 filed on February 7, 2019 discloses the combined parameters of culturing the PBMCs in vitro for a period of 1-2 weeks in the presence of:
i) IL-2 at a concentration of 175 U/ml;
ii) anti-CD3 antibodies; and
iii) 2-DG at a concentration of 2mM (e.g. Example 1).
Accordingly, the effective priority date of the instant Claim 1 is granted as August 6, 2020, the filing date of the instant application.
If applicant believes the earlier applications provide support for this disclosure, applicant should point out such support with particularity by page and line number in the reply to this Action.
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.
1. The prior rejection of Claim(s) 1 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, is withdrawn in light of Applicant’s amendment to the claim to recite the step(s) of culturing the PBMCs in vitro for a period of 1-2 weeks in the presence of:
i) IL-2 at a concentration of 175 to 2000 U/ml;
ii) anti-CD3 antibodies; and
iii) 2-DG at a concentration of 0.5 to 5mM.
Applicant admits that activating alpha/beta T (syn. abT) cells by culturing with anti-CD3 antibodies is well-known in the art, and thus reciting a working concentration is not necessary.
Thus, the anti-CD3 antibody concentration is not considered dispositive for the recited functional limitations.
Applicant argues that the positively recited working concentrations of IL-2 and 2DG, in combination with the generically recited anti-CD3 antibodies, connects the recited functional limitations directly to the method steps.
New matter
2. Claim(s) 1 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Applicant has amended Claim 1 to recite the step(s) of culturing the PBMCs in vitro for a period of 1-2 weeks in the presence of:
i) IL-2 at a concentration of 175 to 2000 U/ml;
ii) anti-CD3 antibodies; and
iii) 2-DG at a concentration of 0.5 to 5mM.
Clear support for the new limitation(s) cannot be found in the instant application or priority documents. Accordingly, the amendment(s) to Claim 1 is considered to constitute new matter.
MPEP 2163.06 notes “If new matter is added to the claims, the examiner should reject the claims under 35 U.S.C. 112, first paragraph - written description requirement. In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981).” MPEP 2163.02 teaches that “Whenever the issue arises, the fundamental factual inquiry is whether a claim defines an invention that is clearly conveyed to those skilled in the art at the time the application was filed...If a claim is amended to include subject matter, limitations, or terminology not present in the application as filed, involving a departure from, addition to, or deletion from the disclosure of the application as filed, the examiner should conclude that the claimed subject matter is not described in that application”. MPEP 2163.06 further notes “When an amendment is filed in reply to an objection or rejection based on 35 U.S.C. 112, first paragraph, a study of the entire application is often necessary to determine whether or not “new matter” is involved. Applicant should therefore specifically point out the support for any amendments made to the disclosure” (emphasis added).
Applicant argues that support for the new limitation(s) may be found in [0020, 23, 70, 73] and Examples 7.5 and 8.1.
Example 7.5 [0070] fails to disclose the 2-DG concentration, and furthermore, the experimental conditions disclose IL-2 concentrations of up to 250 U/ml, not the presently recited 2000 U/ml.
While Example 8.1 [0073] discloses the use of 0 to 4mM 2-DG, such is in the context of a different experimental assay, galectin-3 binding ability, and is absent the use of IL-2 and/or anti-CD3 antibodies.
While [0020] discloses the range of 100 to 2000 IU/ml IL-2, such is silent to the combination of 2-DG concentration of 0.5 to 5 mM.
While [0023] discloses the generic drug may be 5mM or less, more preferably 2mM, such is silent to the combination of IL-2 concentration of 175 to 2000 IU/ml.
As discussed in the prior Office Action, at best, Applicant’s working example (pg 13, Example 1, [0037]) performs the method using 175 IU/ml IL-2 and 2mM 2-DG.
Alternatively, if Applicant believes that support for new limitation(s) as now recited in Claim 1, is present and clearly envisaged in the instant application or earlier filed priority documents, applicant must, in responding to this Office Action, point out with particularity, where such support may be found.
Declarations and new references cannot demonstrate possession of a concept after the fact.
Applicant does not indicate where these limitations are supported by the original specification, or how, as is Applicant's burden. See MPEP §714.02, last sentence of the third paragraph from the end and MPEP §2163.06 (I) last sentence.
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.
3. The prior rejection of Claim 1 under AIA 35 U.S.C. 103 as being unpatentable over Colosimo (2012; of record) in view of Teschner et al (2011; of record), Haas et al (available online July 16, 2015; of record), Secinaro et al (available online January 19, 2018; of record), and Brooks et al (1993; of record) is withdrawn in light of Applicant’s amendments to the claim, necessitating new grounds of rejection.
4. Claim 1 is rejected under AIA 35 U.S.C. 103 as being unpatentable over Colosimo (2012; of record) in view of Brincks et al (F1000 Biology Reports 2:e67, 3 pages, doi:10.3410/B2-67, September 8, 2010), Zinser et al (Human MAIT cells show metabolic quiescence with rapid glucose-dependent upregulation of granzyme B upon stimulation, Immunol. & Cell Biology 96: 666-674, available online February 9, 2018; of record), Teschner et al (2011; of record), Haas et al (available online July 16, 2015; of record), Secinaro et al (available online January 19, 2018; of record), Renner et al (Metabolic plasticity of human T cells: Preserved cytokine production under glucose deprivation or mitochondrial restriction, but 2-deoxy-glucose affects effector functions, Eur. J. Immunol. 45: 2504-2516, 2015), Welte et al (Interleukin 2 regulates the expression of Tac antigen on peripheral blood T lymphocytes, J. Exp. Med. 160(5): 1390-1403, 1984), Yamaguchi et al (A simple method for the propagation and purification of gdT cells from the peripheral blood of glioblastoma patients using solid-phase anti-CD3 antibody and soluble IL-2, J. Immunol. Methods 205: 19-28, 1997), and Brooks et al (1993; 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, Colosimo is considered relevant prior art for having taught an in vitro method of preparing a cell population comprising activated alpha/beta T cells, the method comprising the step(s) of in-vitro culturing PBMCs in the presence of:
i)10-50 IU/ml IL-2;
ii) mb15 feeder cells (used to activate the PBMCs); and
iii) 10mM 2-DG (e.g. pg s 7-8, joining para);
for a period of at least 8 to 15 days (e.g. pg 7, Cell Cultures; pg 20; Figure 11, legend; Figure 12).
Brincks et al is considered relevant prior art for having taught that IL-15 inherently activates alpha/beta T cells per natural law of cell biology (e.g. pg 1, col. 1, Introduction).
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Zinser et al is considered relevant art for having taught an in-vitro method comprising the steps of culturing an isolated peripheral blood mononuclear cells in the presence of:
i) 50ng IL-12 (which is equivalent to about 110 IU/ml ((50ng/ml)(2.18 IU/ng)),
ii) an anti-CD3 antibody, and
iii) 2mM 2-deoxy-d-glucose (2-DG),
for a period of at least 20 hours (pg 673, col. 1, Materials and Methods, In vitro stimulations).
Teschner et al is considered relevant prior art for having taught an in vitro cell culture method of preparing a cell population comprising activated alpha/beta T cells comprising the step(s) of culturing isolated peripheral blood mononuclear cells in the presence of:
i) 100 IU/ml IL-2; and
ii) an anti-CD3 antibody,
for a period of at least 7, 10, or 13 days (e.g. Figure 1, legend, PBMCs, in vitro stimulation with anti-CD3 and IL-2).
Teschner et al taught that PBMC-derived T cells expanded to significantly greater numbers (e.g. 15-fold; pg 157, col. 1) when stimulated with anti-CD3 and IL-2, as compared to IL-2 alone.
Haas et al is considered relevant prior art for having taught an in vitro culture method comprising the steps of in-vitro culturing a population of CD4+ or CD8+ T cells, isolated from a peripheral blood mononuclear cell population (e.g. pg16, Materials and Methods, T cell isolating, in vitro activation), for a period of about 12 hours (overnight) and in the presence of:
i) 10ng/ml IL-2 (which is equivalent to about 22 IU/ml ((10ng/ml)(2.18 IU/ng) = 21.8 IU/ml)),
ii) an anti-CD3 antibody, and
iii) 1mM 2-DG (e.g. pg 16, Methods; Figure 3, legend, “activated CD4+ T cells pretreated with 2-deoxyglucose”; “activated CD4+ T cells in the presence of… 2-DG”; pg16, Materials and Methods, T cell isolating, in vitro activation, “activated…with anti-CD3…, and IL-2”).
Secinaro et al is considered relevant prior art for having taught a method comprising the steps of in-vitro culturing anti-CD3/ 50U/ml IL-2 activated T cells for 3 days in the presence of:
i) 50 U/ml IL-2; and
iii) 5mM 2-DG,
for a period of at least 3 to 6 days (e.g. pg 10, col. 1, Materials and Methods, Cell Culture; Figure 4; pg 6, col. 1, “Day 6”).
Secinaro et al taught that the T cells were CD4+ T cells (e.g. pg 4, col. 2; pg 12, col. 1, Methods, CD4+ T cell)
Secinaro et al taught that resting T cells undergo a rapid metabolic shift to glycolysis upon activation in the presence of IL-2 (Abstract), and that the metabolic activity of effector T cells helps determine their subset differentiation (e.g. pg 1, col. 2, Introduction).
Secinaro et al taught that IL-2 stimulation promotes glycolysis in glycolytic effector T cells, which in turn promotes caspase-3 activation and increases sensitivity to restimulation-induced cell death (RICD). The use of a glycolysis inhibitor, i.e. 2DG, reduces caspase-3 activity as well as sensitivity to RICD (Abstract).
Renner et al is considered relevant prior art for having taught a method of preparing a population of activated alpha/beta CD4+ and CD8+ T cells, the method comprising the step(s) of culturing alpha/beta CD4+ and CD8+ T cells, isolated from PBMCs, for 12 days (pg 2505, col. 2, stimulated for 6 days, then another 6 days) in a culture medium comprising:
i) 100 IU/ml IL-2;
ii) anti-CD3 antibodies; and
iii) 1, 5, or 10mM 2-DG (e.g. Figure 4, legend).
The cited prior art taught wherein the PBMCs and/or alpha/beta T cells are cultured with IL-2 at a concentration of 10, 22, 50, 100, and 110 U/ml IL-2.
Neither Colosimo et al, Zinser et al, Teschner et al, Haas et al, Secinaro et al, nor Renner et al teach wherein the PBMCs and/or alpha/beta T cells are cultured with IL-2 at a concentration of at least 175 U/ml.
However, prior to the effective filing date of the instantly claimed invention, Welte et al is considered relevant prior art for having taught a method of preparing a population of activated alpha/beta CD4+ and CD8+ T cells, isolated from PBMCs, the method comprising the step(s) of culturing the isolated alpha/beta CD4+ and CD8+ T cells for at least 3 days in a culture medium comprising:
i) 20, 200, or 2,000 IU/ml IL-2;
ii) anti-CD3 antibodies (e.g. pg 1392, Methods; Table IV),
whereby the relative amounts of DNA synthesis, an indicator of cellular replication, is substantially the same at all three concentrations.
Similarly, Yamaguchi et al is considered relevant prior art for having taught a method of preparing a population of T cells, the method comprising the step(s) of culturing PBMCs for at least 4-5 days to as many as 14 days (Figure 2, legend) in a culture medium comprising:
i) 700 IU/ml IL-2;
ii) anti-CD3 antibodies (e.g. pg 21, col. 1, Methods, Cell propagation).
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, culturing peripheral blood cell populations, and culturing peripheral blood T cell populations. 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.
Brooks et al is considered relevant prior art for having taught that “most human T cells express alpha/beta TCR and either CD4 or CD8 molecules” (Abstract).
Those of ordinary skill in the art would have reasonably inferred and/or recognized that the PBMC cell populations of Colosimo and Teschner et al naturally comprise alpha/beta T cells.
Those of ordinary skill in the art would have reasonably inferred and/or recognized that the PBMC-derived CD4+ or CD8+ T cell populations of Haas et al and Secinaro et al naturally comprise alpha/beta T cells.
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 substitute a first means of activating alpha/beta T cells in a PBMC cell population, e.g. mb15 feeder cells in combination with IL-2 and 2-DG, as taught by Colosimo, with a second means of activating alpha/beta T cells in a PBMC cell population, i.e. anti-CD3 antibodies in combination with IL-2, as taught by Teschner et al, Haas et al, Secinaro et al, and Renner et al, including the use of 2-DG, as taught by Zinser et al, Haas et al, and Renner et al, in a method of preparing a PMBC cell population comprising activated alpha/beta T cells with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute mb15 feeder cells in combination with IL-2 and 2-DG with anti-CD3 antibodies in combination with IL-2 and 2-DG in a method of preparing a PMBC cell population comprising activated alpha/beta T cells because those of ordinary skill in the art had long-recognized and routinely used anti-CD3 antibodies in combination with IL-2 in a method of preparing a PMBC cell population comprising activated alpha/beta T cells, whereby the combination of IL-2 and 2-DG, the combination of anti-CD3 antibodies and 2-DG, and the combination of anti-CD3 antibodies, IL-2 and 2-DG, had been successfully demonstrated when culturing PBMC-derived alpha/beta T cells.
As discussed above, Applicant admits that activating alpha/beta T cells by culturing with anti-CD3 antibodies is well-known in the art. Thus, the anti-CD3 antibody concentration is not considered dispositive for the recited functional limitations.
Thus, those of ordinary skill in the art previously recognized and successfully reduced to practice the scientific and technical concept(s) of culturing PBMCs and/or alpha/beta T cells isolated from PBMCs in the presence of an interleukin, including IL-2 in combination with 2-DG, and anti-CD3 antibodies, whereby the anti-CD3 antibodies have long-been art-recognized to activate alpha/beta T cells, as is also achieved using mbIL-15 per Colosimo et al.
It is well known that it is prima facie obvious to combine two or more ingredients (IL-2 and 2-DG; anti-CD3 antibodies and IL-2; anti-CD3 antibodies and 2-DG; stimulatory agent, IL-2, and 2-DG; anti-CD3 antibodies, IL-2, and 2-DG) each of which is taught by the prior art to be useful for the same purpose in order to form a third composition (anti-CD3 antibodies, IL-2, and 2-DG) which is useful for the same purpose (as well as to use such a composition for that purpose - i.e., an in vitro culture method to stimulate T cells). The idea for combining them flows logically from their having been used individually in the prior art, and from them being recognized in the prior art as useful for the same purpose. This rejection is based on the well-established proposition of patent law that no invention resides in combining old ingredients of known properties where the results obtained thereby are no more than the additive effect of the ingredients. In re Kerkhoven, 626 F.2d 846, 850, 205 U.S.P.Q. 1069 (CCpA 1980), In re Sussman, 1943 C.D. 518; In re Pinten, 459 F.2d 1053, 173 USPQ 801 (CCPA 1972); In re Susi, 58 CCPA 1074, 1079-80; 440 F.2d 442, 445; 169 USPQ 423,426 (1971); In re Crockett, 47 CCPA 1018, 1020-21; 279 F.2d 274, 276-277; 126 USPQ 186, 188 (1960). The step of culturing PBMC comprising alpha/beta T cells, and/or alpha/beta T cells isolated from PBMCs, in a combination of a cytokine stimulatory agent, IL-2, and 2-DG was previously known and successfully reduced to practice by the ordinary artisans (e.g. Colosimo et al, Zinser et al, Haas et al, Renner et al). The step of culturing alpha/beta T cells in a combination of anti-CD3 antibodies, IL-2, and 2-DG was previously known and successfully reduced to practice by the ordinary artisans (e.g. Haas et al, Renner et al).
Secinaro et al taught that IL-2 stimulation promotes glycolysis in glycolytic effector alpha/beta T cells, which in turn promotes caspase-3 activation and increases sensitivity to restimulation-induced cell death (RICD). The use of a glycolysis inhibitor, i.e. 2-DG, reduces caspase-3 activity as well as sensitivity to RICD (Abstract).
Colosimo taught culturing the PBMCs for a period of at least 8 to 15 days.
Teschner et al taught culturing the PBMCs for a period of at least 7, 10, or 13 days.
Secinaro et al taught culturing the T cells for a period of at least 3 to 6 days.
Renner et al taught culturing the T cells isolated from PBMCs for a period of at least 12 days.
Welte et al taught culturing the T cells isolated from PBMCs for a period of at least 3 days.
Yamaguchi et al taught culturing the PBMCs for a period of at least 4-5 days to as many as 14 days.
The prior art taught a culturing range of 3, 4, 5, 6, 7, 8, 10, 12, 13, or 15 days.
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).
Instant specification fails to disclose an element of criticality for a period of 7-14 days, as opposed to the culturing range of 3, 6, 7, 8, 10, 12, 13, or 15 days taught by the cited prior art.
Colosimo et al taught culturing the PBMCs with 10 or 50 IU/ml IL-2.
Zinser et al taught culturing the PBMCs with about 110 IU/ml IL-2.
Teschner et al taught culturing the PBMCs with 100 IU/ml IL-2.
Haas et al taught culturing CD4+ or CD8+ T cells isolated from PBMCs with about 22 IU/ml IL-2.
Secinaro et al taught culturing T cells with 50 U/ml IL-2.
Renner et al taught culturing alpha/beta CD4+ or CD8+ T cells isolated from PBMCs with 100 IU/ml IL-2.
Welte et al taught culturing alpha/beta CD4+ or CD8+ T cells isolated from PBMCs with 20, 200, or 2,000 IU/ml IL-2.
Yamaguchi et al taught culturing PBMCs with 700 IU/ml IL-2.
The prior art taught culturing PBMCs and/or alpha/beta T cells isolated from PBMCs, with IL-2 at a concentration range of 10, 20, 22, 50, 100,110, 200, 700, or 2,000 U/ml.
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).
Instant specification fails to disclose an element of criticality for the IL-2 range of 175 to 2000 U/ml, as opposed to the IL-2 culturing range of 10, 20, 22, 50, 100,110, 200, 700, or 2,000 U/ml taught by the cited prior art.
The IL-2 concentrations, 2-DG concentrations, and length of culturing are each parameters recognized by the ordinary artisans to be result-effective variable, i.e., a variable which achieves a recognized result, routinely modified touching and/or within the instantly recited parameters, whereby optimum or workable ranges of said variables is characterized as routine experimentation. In reAntonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977), In reBoesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980). (See MPEP2144.05).
Instant specification fails to disclose an element of criticality for the use of 175-2000 U/ml IL-2 in combination with 0.5-5mM 2-DG for at least 7 days, as opposed to:
10 IU/ml IL-2 in combination with 10mM 2-DG for 8-15 days (Colosimo et al);
22 IU/ml IL-2 in combination with 1mM 2-DG (Haas et al);
50 IU/ml IL-2 in combination with 10mM 2-DG for 8-15 days (Colosimo et al);
50 IU/ml IL-2 in combination with 5mM 2-DG for 3-6 days (Secinaro et al);
100 IU/ml IL-2 in combination with 1mM 2-DG for 12 days (Renner et al);
100 IU/ml IL-2 in combination with 5mM 2-DG for 12 days (Renner et al);
100 IU/ml IL-2 in combination with 10mM 2-DG for 12 days (Renner et al); and/or
110 IU/ml IL-12 in combination with 2mM 2-DG for about 1 day (Zinser et al),
taught by the cited prior art.
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).
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 the combination of 2-DG when IL-2 is present at a concentration of at least 175 U/ml is not taught or suggested by the prior art.
Applicant’s argument(s) has been fully considered, but is not persuasive. The IL-2 concentrations, 2-DG concentrations, and length of culturing are each parameters recognized by the ordinary artisans to be result-effective variable, i.e., a variable which achieves a recognized result, routinely modified touching and/or within the instantly recited parameters, whereby optimum or workable ranges of said variables is characterized as routine experimentation. In reAntonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977), In reBoesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980). (See MPEP2144.05).
Instant specification fails to disclose an element of criticality for the use of 175-2000 U/ml IL-2 in combination with 0.5-5mM 2-DG for at least 7 days, as opposed to:
10 IU/ml IL-2 in combination with 10mM 2-DG for 8-15 days (Colosimo et al);
22 IU/ml IL-2 in combination with 1mM 2-DG (Haas et al);
50 IU/ml IL-2 in combination with 10mM 2-DG for 8-15 days (Colosimo et al);
50 IU/ml IL-2 in combination with 5mM 2-DG for 3-6 days (Secinaro et al);
100 IU/ml IL-2 in combination with 1mM 2-DG for 12 days (Renner et al);
100 IU/ml IL-2 in combination with 5mM 2-DG for 12 days (Renner et al);
100 IU/ml IL-2 in combination with 10mM 2-DG for 12 days (Renner et al); and/or
110 IU/ml IL-12 in combination with 2mM 2-DG for about 1 day (Zinser et al),
taught by the cited prior art.
Applicant iterates prior arguments.
The Examiner has rebutted said prior arguments in prior Office Actions.
Conclusion
5. 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