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 .
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This Action is in response to the papers filed on 03/31/2026. Claims 1, 21-30, and 32-35 are currently pending. Claims 2-20 were previously canceled as per claims filed on 06/02/2022. Claims 1, 21-28, 30, and 35 have been amended and claim 31 has been cancelled by Applicant’s amendment filed on 03/31/2026.
Election/Restrictions
Applicant’s election of species, without traverse, of ipilimumab, in the reply filed on 08/04/2025 was previously acknowledged.
Claims 23 and 25 were withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.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. Therefore, claims 1, 21-22, 24, 26-30, and 32-35 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.
Withdrawn Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 102
The rejection of claims 1, 18, 19, 27, 30, and 43 under 35 USC § 102 is withdrawn in view of the amendments in the response filed on 03/31/2026. Arguments drawn to a withdrawn rejections are considered moot.
The rejection of claims 27 and 28 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filing priority date 11/06/2017; IDS filed 03/13/2024; hereafter “Bobisse”) as applied to claim 1 above has been withdrawn.
A response to Applicant’s arguments with regard to a withdrawn rejection is moot. A response to any argument pertaining to a new or maintained rejection can be found below.
Maintained or modified rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 112 (b)
Claims 1, 21-22, 24, 26-30, and 32-35 remain 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.
This rejection is necessitated in response to applicants’ amendments filed 03/31/2026.
Claim 1 recites the following phrase, “…in a cell culture medium comprising IL-2 and three or more Tumor Microenvironment (TME) stimulators to produce an expanded population of TILs, wherein the three or more TME stimulators are selected from the group consisting of pembrolizumab, ipilimumab, urelumab, and/or utomilumab, wherein the three /or more TME stimulators are added to the cell culture medium simultaneously or between 1, 2, 3, 4, 5, 6, or 7 days apart…”.
It is unclear what the intended determination of TME stimulator selection with respect to “…wherein the three or more TME stimulators are selected from the group consisting of pembrolizumab, ipilimumab, urelumab, and/or utomilumab, wherein the three or more TME stimulators are added to the cell culture medium simultaneously or between 1, 2, 3, 4, 5, 6, or 7 days apart…”. As written, the claim does not preclude the use of a single TME provided 3 times. Does the applicant intend that 3 or 4 separate and distinct TME stimulators are selected? The metes and bounds are unclear and therefore the claim is rendered indefinite. The examiner recommends amending claim 1 to recite a proper Markush group. A proper format requires the use of the conjunction “and” before the final member of the group.
Additionally, it is unclear when exactly TME stimulators can be provided to the cells. Can one administration happen every 7 days? Are the days counted in respect to the cells plating? The first agent administration? Each successive administration of an agent? One of ordinary skill in the art would not be reasonably appraised of the metes and bounds with respect to how and when the TME stimulators can be used, therefore the claim is indefinite.
Claim 28 is indefinite in its recitation of “ the second expanded population of TILs” in line 2. There is not proper antecedent bases for the phrase “the second expanded population of TILs”.
Claim 30 is indefinite in its recitation of “ the second expanded population of TILs” in line 2. There is not proper antecedent bases for the phrase “the second expanded population of TILs”.
Claim 30 has been amended to recite “population of TILs”. Claim 30 is indefinite in its recitation of “cells” in line 3. There is not proper antecedent bases for “the cells” in the claim.
Claim 35 has been amended to recite “population of TILs”. Claim 35 is indefinite in its recitation of “cells” in line 2. There is not proper antecedent bases for “the cells” in the claim or parent claim1.
Claims 21-22, 24, 26-27, 29, and 32-34 are rejected insofar as they depend from claim 1.
New rejections in response to Applicants’ arguments or amendmentsClaim 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.
Claims 1, 21-22, 24, 26-30, and 32-35 are newly rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
This rejection is necessitated in response to applicants’ amendments filed 03/31/2026.
Amended claim 1 recites the following: “A method for expanding tumor infiltrating lymphocytes (TILs) into a therapeutic population of TILs comprising: culturing TILs obtained from a tumor resected from a mammal in a cell culture medium comprising IL-2 and three or more Tumor Microenvironment (TME) stimulators to produce an expanded population of TILs, wherein the three or more TME stimulators are selected from the group consisting of pembrolizumab, ipilimumab, urelumab, and/or utomilumab, wherein the three /or more TME stimulators are added to the cell culture medium simultaneously or between 1, 2, 3, 4, 5, 6, or 7 days apart; and supplementing the cell culture medium of the expanded population of TILs with additional IL-2, an OKT3 antibody, and antigen presenting cells (APCs), to produce therapeutic population of TILs.”
The instant disclosure fails to provides support pertaining a method of expanding TILs comprising culturing with all possible drug and drug dosing timeframe combinations of pembrolizumab, ipilimumab, urelumab, and/or utomilumab administered at between all possible timeframes of “between 1, 2, 3, 4, 5, 6 or 7 days apart”. There is not structure/ function correlation for the claimed genus of TILs expanded as recited and their therapeutic function. Specification Disclosure
The specification describes limited examples of specific drug combinations and specific drug administration timeframes. Of these, the experimental data is limited when demonstrating efficacy from more than two specific drugs in combination with IL-2. Of these, only limited combinations using three mABs (and not four), which include IL-2 alone or in combination with a 4-1 BB agonist, urelumab together with anti-CD3 (OKT3) (group J) either alone, or in combination with a CTLA-4 inhibitor, ipilimumab (group B), or in combination with a PD-1 inhibitor, pembrolizumab (group A), or in a triple combination of both ipilimumab and pembrolizumab (Figure 40 of the instant application), it does not provide written support that would enable one having reasonable skill in the art to perform a method of expanding TILs comprising culturing with all possible combinations of pembrolizumab, ipilimumab, urelumab, and/or utomilumab administered at between all possible timeframes of “between 1, 2, 3, 4, 5, 6 or 7 days apart” to obtain expanded therapeutic TILs.
The instant disclosure provides textual support that contemplates the use of multiple groupings, “The groups A-X listed in Table 1 can be combined and used as multiple substances as seen in Tables 2-44. Thus, in one or more embodiments is IL2 used in any of the combination with any of the substances (see Table 1) in the first expansion, i.e. step (b) of the methods of the present invention in any of the combinations listed in Tables 2-44.” However, of tables 2-44, no four drug combinations are discussed, no culture timings are provided, no administration order requirements, and no description on how to predict optimal combinations.
The instant disclosure provides experimental support at Figure 6 (provided below) for a three TME agent (monoclonal antibody) grouping, of J A B. Which represent a 4-1BB/CD137 agonist, PD-1 antagonist, CTLA-4 antagonist, respectively.
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In summary, the specification describes a minimal species within the claimed genus – a method of expanding TILs comprising culturing with all possible combinations of pembrolizumab, ipilimumab, urelumab, and/or utomilumab administered at between all possible timeframes of “between 1, 2, 3, 4, 5, 6 or 7 days apart”.
Guidance Provided by the Art
The prior art was generally searched for isolation and culture method of tumor infiltrating lymphocytes and the usage of the culture components recited in the instant claims including IL-2 and the specific antibodies for expansion of TILs. The search uncovered IL-2 used in combination with some specific monoclonal antibodies as well as multistep culture protocol for expansion of TILs. The closest teachings being Bobisse et al. (See also 103 rejections below).
Bobisse. (WO 2019/086711 A1, publication date 9 May 2019) teaches a multi-step culture 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]). Bobisse explicitly teaches the lymphocytes cultured may be autologous (Pg. 23, Paragraph [0211]). The subject refers to mammal, including humans (Pg. 8, Paragraph [0085]).
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]). 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]).
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]).
Bobisse teaches more than one expansion agent (reading on the instant 3 or more TME stimulators) may be used within their method of cell expansion, these include antibodies against PD-1, ctla-4, and 4-1BBB with IL-2 (Pg. 3, Paragraph [0025]).
However, Bobisse does not teach the specific drugs/mABs of pembrolizumab (anti-PD-1) and Urelumab (agonistic anti-4-1BB antibody of CD137) or all possible combinations claimed broadly in the instant claim 1. The breadth of claim 1 creates a substantial combinatorial burden within the claimed genus. The recited alternatives permit multiple independent variables including identity of TME stimulators, the number of TME stimulators used, and the day and days of administration to obtain expanded TILs having a therapeutic function. Claim 1 does not preclude the use of a single-agent three times, claim 1 does not provide an order to which the agents can be administered. (see also 112b with respect to claim 1.).
Thus, the art fails to provide any additional species within the claimed genus that would provide one having ordinary skill in the art the capacity to understand which combinations of TMEs and combinations of possible dosing schedule would allow for successful expansion of TILs.
Conclusion
Considering the large variation in the genus, the minimal species described in the specification, and the lack of predictability provided by the specification and art for the full scope of the claimed genus, it is reasonable to conclude that Applicant did not possess the invention as claimed at the time of filing. Claim Rejections - 35 USC § 103
Claims 1, 21-22, 24, 26-30, and 32-35 are newly rejected under 35 U.S.C. 103 as being unpatentable under 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.) in view of Sarnaik et al. (US20170044496A1, IDS filed as on 3/13/2024 as WO 2015/157636 Al; hereafter “Sarnaik”) and in view of Kunimasa et al. (Kunimasa K. et al., Isei T, Invest New Drugs, 2018; here after “Kunimasa”).
This rejection is necessitated in response to the claim amendments filed 03/31/2026.
Claim 1 of the instant application is provided below for ease of reference.
Amended claim 1 recites the following: “A method for expanding tumor infiltrating lymphocytes (TILs) into a therapeutic population of TILs comprising: culturing TILs obtained from a tumor resected from a mammal in a cell culture medium comprising IL-2 and three or more Tumor Microenvironment (TME) stimulators to produce an expanded population of TILs, wherein the three or more TME stimulators are selected from the group consisting of pembrolizumab, ipilimumab, urelumab, and/or utomilumab, wherein the three or more TME stimulators are added to the cell culture medium simultaneously or between 1, 2, 3, 4, 5, 6, or 7 days apart; and supplementing the cell culture medium of the expanded population of TILs with additional IL-2, an OKT3 antibody, and antigen presenting cells (APCs), to produce therapeutic population of TILs.”
Regarding Claim 1 and 24, Bobisse teaches a multi-step culture 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]). Bobisse explicitly teaches the lymphocytes cultured may be autologous (Pg. 23, Paragraph [0211]). The subject refers to mammal, including humans (Pg. 8, Paragraph [0085]).
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]). 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]).
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]).
Bobisse teaches more than one expansion agent (reading on the instant claim 1 requirement for 3 or more TME stimulators) may be used within their method of cell expansion, these include antibodies against PD-1, ctla-4, and 4-1BBB with IL-2 (Pg. 3, Paragraph [0025]).
However, Bobisse does not teach the specific drugs/mABs of pembrolizumab (anti-PD-1) and Urelumab (agonistic anti-4-1BB antibody of CD137). Sarnaik teaches the use of IL-2 and a 41BB agonist used in combination with anti-PD-1 antibody and anti-CTLA-4 antibody for the expansion of Tils (Claims 1-5 of Sarnaik). Sarnaik teaches BMS 663513 (alias of Urelumab) as an embodiment of agonistic anti-4-1BB antibody (Paragraph [107]).
Although both Bobisse and Sarnaik teach the use of anti-PD-1 mABs for expansion of Tils, neither specifically mention the use of the anti-PD-1 mAB pembrolizumab.
However, it was known in the art at the time of the instant application that targeting PD-1 using pembrolizumab specifically would induce a proliferative state for T cells. Kunimasa teaches that “PD-1 is a major regulator of T-cell exhaustion, and pembrolizumab reinvigorates T-cells, leading to a proliferative state” (Discussion, 3rd Paragraph). Further, Kunimasa teaches that pembrolizumab has a documented clinical effect in human patients and a well-known safety profile (Introduction, 1st Paragraph).
It would have therefore been prima facie obvious to a person having ordinary skill in the art at the time of the instant application to use multiple antibodies in a combination previously shown to successfully expand culture of TILs (such as taught by Bobisse and Sarnaik) and to further modify these teachings by selecting a specific anti-PD-1 drug such as a clinically approved pembrolizumab (such as taught by Kunimasa) to produce an expected additive effect in to produce a therapeutic population of TILs.
One would have been motivated to combine these teachings as Bobisse and Sarnaik both provide the framework for the claimed combination of antibodies and IL-2 in a method for expansion of TILs and selecting the specific antibodies that are well characterized and have clinical data, such as pembrolizumab as taught by Kunimasa, would have been a routine optimization yielding predictable results.
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, Sarnaik, and Kunimasa together render obvious the method of claim 1. Bobisse and Sarnaik teach some working ranges and concentration optimization of antibodies used. Bobisse teaches the anti-CTLA-4 and anti-PD1 antibodies are routinely used at 10 µg/mL in combination with IL-2 (Pg. 4, Paragraph [0038]; Pg. 6, Last line of Paragraph [0048]). Sarnaik teaches the use of 10 mg/ml anti-4-lBB antibody was found to optimal and induced the highest TIL expansion in initial experiments on 3 different melanoma patient tumors (Figure 8 of Sarnaik).
However, Bobisse, Sarnaik, and Kunimasa do not specifically teach all of the ranges of the instant application claim 26.
A person of ordinary skill in the art would have been motivated to determine an appropriate concentration for the combination of antibodies through routine optimization within a culture method for the expansion of TILs, in order to effectively achieve a desired population of said TILs.
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[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) (MPEP 2144.05 (II) (A)).
It is a settled principle of law that a mere carrying forward of an original patented conception involving only a change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not an invention as will sustain a patent, even though the changes of the kind may produce better than expected results than prior inventions” In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) (see MPEP 2144.05).
Applicant has not provided any empirical evidence that the instantly claimed concentrations are critical to the instantly claimed invention. "The law is replete with cases in which the difference between the claimed invention and the prior art is some range or other variable within the claims. . . . In such a situation, the applicant must show that the particular range is critical, generally by showing that the claimed range achieves unexpected results relative to the prior art range." In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See also Minerals Separation, Ltd. v. Hyde, 242 U.S. 261, 271 (1916) (a patent based on a change in the proportions of a prior product or process (changing from 4-10% oil to 1% oil) must be confined to the proportions that were shown to be critical (1%)); In re Scherl, 156 F.2d 72, 74-75, 70 USPQ 204, 205 (CCPA 1946) ("Where the issue of criticality is involved, the applicant has the burden of establishing his position by a proper showing of the facts upon which he relies."); In re Becket, 88 F.2d 684 (CCPA 1937).
Regarding Claims 27 and 28, Bobisse, Sarnaik, and Kunimasa together render obvious the method of claim 1. Moreover, 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. 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. Sarnaik and Kunimasa do not provide exact time frames for this culture step.
A person of ordinary skill in the art would have been motivated to determine an appropriate timeframe to perform the culture steps of preREP and REP 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.
Regarding Claim 29, Bobisse, Sarnaik, and Kunimasa together render obvious the method of claim 1. Moreover, 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, Sarnaik, and Kunimasa together render obvious the method of claim 1. Moreover, Bobisse teaches that their culture methodology can produce a final number of TILs to the order of 109 -1011 (Pg. 1, Paragraph [0006]), which reads on the range of instant claim 30.
Regarding Claim 32, Bobisse, Sarnaik, and Kunimasa together render obvious the method of claim 1. Moreover, Bobisse teaches the use of APCs that are PBMCs (Pg. 11, Paragraph [0107]).
Regarding Claims 33-34, Bobisse, Sarnaik, and Kunimasa together render obvious the method of claim 1. Moreover, 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, Sarnaik, and Kunimasa together render obvious the method of claim 1. Moreover, 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.
Response to Applicants’ arguments as they pertain to the new rejection of claims 1, 21-22, 24, 26-30, and 32-35 under 35 U.S.C. 103
At page 6 of Applicants’ response filed on 03/31/2026, Applicants’ essentially argue that amended claim 1 is not anticipated by Bobisse. Applicant provides the following “Applicant has amended claim I as shown above to further require that the cell culture medium comprise three or more TME stimulators, which may be added together or over time. Support for this amendment can be found throughout the specification as filed, including, for example, at paragraphs [0057], [0063], [0064], [0073], [0119], [0152], [0202], [0226], Fig. 6, and Fig. 39. Applicant respectfully submits that Bobisse does not teach or suggest each and every element of presently amended claim 1. Claim I is therefore novel over Bobisse for at least this additional reason. Claims 21, 22, 24, 26-30, and 32-25 depend directly or indirectly on claim 1 and are therefore novel over Bobisse for at least this same reason.”
Similarly, applicant argues that Pg. 6-7 that the rejection of claims 27-28 under 35 U.S.C. 103 as being unpatentable over Bobisse should be withdrawn as Bobisse does not teach the amended claim 1.
Examiner concedes that Bobisse does not teach all elements of the amended claim 1. However, Bobisse in view of Sarnaik and in view of Kunimasa render obvious the amended claim 1 and its dependent claims as discussed above in the new 103 rejection above.
Conclusion
Claims 1, 21-22, 24, 26-30, and 32-35 are rejected. 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.
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
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