DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
This action is in response to the papers filed on 08/04/2025. Claims 1 and 21-35 are currently pending as per claims filed on 06/02/2022. Claims 2-20 were previously canceled as per claims filed on 06/02/2022.
Applicant’s election of species, without traverse, of ipilimumab, in the reply filed on 08/04/2025 is acknowledged.
Claims 23 and 25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08/04/2025.
The requirement for restriction between species is still deemed proper and is therefore made FINAL.
Therefore, claims 1, 21-22, 24, 26-35 are subject to examination to which the following grounds of rejection are applicable.
Priority
This application is a 371 of PCT/EP2020/087151 filed on 12/18/2020, which claims foreign priority EP 19217356.5 filed on 12/18/2019.
Thus, the earliest possible priority for the instant application is 12/18/2019.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 06/29/2022, 10/31/2023, 03/13/2024, 08/14/2024 and 09/08/2025 were filed before the mailing date of the non-final office action. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 21-22, 24, 26-35 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 is rejected under 35 U.S.C. 112, second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention. Claim 1 recites the broad recitation “TILs”, and the claim also recites “T cells” which is the narrower statement of the range/limitation.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) is considered indefinite, since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
Claim 31 recites “The method of claim 1, wherein the TME stimulators are added together or 1, 2, 3, 4, 5, 6 or 7 days apart.” It is unclear what the intended meaning of “added together” is. Therefore, the metes and bounds cannot be established. Thus, the claim is indefinite. The method of claim 1 recites multiple steps and components. What step or component is the stimulator added together with? As such the metes and bounds of the claim are indefinite.
Claims 1, 21-22, 24, 26-30, 32-35 are indefinite insofar as they depend on claim 1.
Claim Interpretation
Claim 1 of the instant application recites: “A method for expanding tumor infiltrating lymphocytes(TILs) into a therapeutic population of TILs comprising:
(a) culturing autologous T cells by obtaining a first population of tumor infiltrating lymphocytes from a tumor resected from a mammal
(b) performing a first expansion by culturing the first population of TILs in a cell culture medium comprising IL-2 and one or more Tumor Microenvironment (TME) stimulators to produce a second population of TILs[[;]] , wherein the one or more TME stimulators are selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, sym02 l, atezolizumab, avelumab, durvalumab, ipilimumab, tremelimumab, urelumab and utomilumab; and
(c) performing a second expansion by supplementing the cell culture medium of the second population of TILs with additional IL-2, an OKT3 anti CD3 antibody, and antigen presenting cells (APCs), to produce a third population of TILs, wherein the third population of TILs is a therapeutic population”
Regarding step (a), a method of obtaining TILs from a tumor resected from a mammal would require that culturing of the autologous T cells is already being performed during that step. Therefore, the culturing of autologous T cells is intrinsic to the method as they are present in the culture with the resected tumor. Any teaching that details the method of culturing a resected tumor for the purpose of obtaining autologous T cells will be considered.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 21-22, 24, 26-30, and 32-35 are rejected under 35 U.S.C. 102 as being anticipated by Bobisse et al. (WO 2019/086711 A1, publication date 9 May 2019; earliest filing priority date 11/06/2017; IDS filed 03/13/2024; hereafter “Bobisse”, Citations are from the National Stage U.S. Pub. 20200338125 A1, The National Stage is deemed an English language translation.).
Regarding Claim 1 and 24, Bobisse teaches a method for expanding lymphocytes
(Abstract; Pg. 1, Paragraph [0003]), including tumor-infiltrating lymphocytes (TILs) (Pg. 3, Paragraph [0026]). The lymphocytes are cultured from samples from a subject, such as from tumor fragments (Pg. 3, Paragraph [0027]). Please see the claim interpretation above regarding culturing of autologous T cells. Bobisse explicitly teaches the lymphocytes cultured may be autologous (Pg. 23, Paragraph [0211]). The subject refers to mammal, including humans (Pg. 8, Paragraph [0085]), falling within the scope of claim 1 step (a).
Bobisse teaches the method of expansion to include an initial expansions phase termed “preREP” and a second expansion phase termed “REP” (Figs. 16A-G; Pg. 10, Paragraph [0097]). preREP as taught by Bobisse anticipates step (b) of instant claim 1 as this culture step is for expansion of the cells obtained (derived from) the subject as described above in the teachings of Bobisse that anticipate step (a). Bobisse describes “preREP” as “a procedure wherein lymphocytes (e.g., derived from a sample for a subject, such as but not limited to, a blood sample, tissue, tumor fragments, or enzymatically digested tissue, dissociated/suspended tumor cells, a lymph node sample, or a bodily fluid sample) are initially expanded over a period of time in culture media supplemented with a compound that ensures continued lymphocyte division and survival during the initial expansion phase.”, and further describes an embodiment of preREP as “takes place in conditions that favor the growth and/or expansion of lymphocytes over tumor and other non-lymphocyte cells. In certain embodiments, the pre-REP procedure occurs in a period of time that lasts between about 3 to about 45 days, about 5 to about 40 days, or about 11 to about 35 days.” (Pg. 8, Paragraph [0079]). Bobisse teaches the use of multiple expansion promoting agents, including interleukins such as IL-2 (Pg. 3, Paragraph [0025]) and antagonists against CTLA-4 (Pg. 10, Paragraph [0098]) during the preREP phase. Bobisse teaches the use of the anti-CTLA-4 mAB Ipilimumab during expansion culture (Pg. 5, Paragraph [0048]). The use of Ipilimumab anticipates claim 24 and step (b) of claim 1.
Bobisse describes the second expansion “REP” as “a procedure that occurs after the pre-REP procedure wherein the lymphocytes ( e.g., derived from a sample for a subject, such as but not limited to, a blood sample, tissue, tumor fragments, or enzymatically digested tissue or tumor cell suspension) are expanded [multiple fold]” (Pg. 8, Paragraph [0080]). Bobisse further teaches embodiments of the second expansion (REP) culture to include the use of IL-2 (Pg. 11, Paragraph [0109]), feeder cells including antigen presenting peripheral blood mononuclear cells (PBMC) (Pg. 11, Paragraph [0107]), and an OKT-3 antibody (Pg. 11, Paragraph 0110]) reading on claim 1 step (c).
Regarding Claim 21, Bobisse teaches administering to the subject an effective amount of the cells produced by the method of the invention (TILs to the order of 109 -1011).
Regarding Claim 22, Bobisse teaches administration to the subject of the cells produced by the invention can occur before, at the same time, or after additional therapeutics, including those used to treat cancer. Bobisse also teaches an exemplary use of non-myeloablative chemotherapy agents (Pg. 25, Paragraph [0225] and [0226]), and lists a large variety of non-limiting examples of therapeutics suitable for use (Pg. 25-26, Paragraph [0227]).
Regarding Claim 26, Bobisse teaches the anti-CTLA-4 mAB Ipilimumab is routinely used at 10 µg/mL in combination with IL-2 (Pg. 4, Paragraph [0038]; Pg. 6, Last line of Paragraph [0048]).
Regarding Claim 29, Bobisse teaches multiple exemplary cancers that the subject to be treated may have, including many recited in the instant claim 29 (Pg. 4, Paragraph [0036]; Pg. 23, Paragraph [0218]).
Regarding Claim 30, Bobisse teaches that the REP culture (which reads on the instant claim 1 step (c)) results in a final number of TILs to the order of 109 -1011 (Pg. 1, Paragraph [0006]), which anticipates the range of instant claim 30.
Regarding Claim 32, Bobisse teaches the use of APCs that are PBMCs (Pg. 11, Paragraph [0107]).
Regarding Claims 33-34, Bobisse teaches use of tumor fragments for obtaining TILs (Pg. 3, Paragraph [0027]; Fig. 16) and further teaches processing of multiple tumor fragments and further teaches using tumor fragments from 1-2 mm3 (Pg. 27, Paragraph [0243]).
Regarding Claim 35, Bobisse teaches lymphocytes produced by the methods described herein can be administered to a subject at a dose ranging from about 107 to about 1012. This anticipates the range of instant claim 35.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 27 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Bobisse et al. (WO 2019/086711 A1, publication date 9 May 2019; earliest filing priority date 11/06/2017; IDS filed 03/13/2024; hereafter “Bobisse”) as applied to claim 1 above.
Regarding Claims 27 and 28, Bobisse teaches the method of claim 1 as described in the 102 rejection above, the contents of which are incorporated herein in their entirety.
Bobisse teaches in certain embodiments, the pre-REP procedure occurs in a period of time that lasts between about 3 to about 45 days, about 5 to about 40 days, or about 11 to about 35 days.” (Pg. 8, Paragraph [0079]). Moreover, Bobisse teaches “In certain embodiments, the second expansion (e.g., REP) procedure occurs in a period of time that lasts between about 5 to about 42 days. In certain embodiments, the second expansion occurs between about 7 to about 35 days, about 10 to about 28 days, or about 14 to about 21 days. In certain embodiments, the second expansion is about 10 days long. In certain embodiments, the second expansion is about 11 days long. In certain embodiments, the second expansion is about 14 days long (Pg. 11, Paragraph [0114]).
However, Bobisse does not clearly define the time frame in which the culture of sample derived from the subject and thus the autologous T cells (which reads instant claim 1, step (a)) occurs. Therefore, the teachings of Bobisse do not seem to provide the exact days the preREP and REP culture steps are occurring with respect the primary culture of the of sample derived from the subject from which the initial cell population is derived.
A person of ordinary skill in the art would have been motivated to determine an appropriate timeframe to perform the culture steps of preREP (reading on claim 1, step (b)) and REP (reading on claim 1, step (c)) through routine optimization, in order to effectively achieve a desired population of TILs.
"[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.") See MPEP 2144.05 II. A.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KODYE LEE ABBOTT whose telephone number is (703)756-1111. The examiner can normally be reached M-F 8-5.
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/KODYE LEE ABBOTT/ Examiner, Art Unit 1634
/MARIA G LEAVITT/ Supervisory Patent Examiner, Art Unit 1634