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
Claims 1-2, 10-12, and 20-26 are pending in the instant application.
Claims 25-26 are new.
Rejections Withdrawn
The rejections to claim 13 is moot in view of claim cancelation.
The rejection of claims 1-2, 10-12, and 20-24 under 35 U.S.C. 112(b) is withdrawn in view of claim amendment.
The rejection of claims 1-2, 10-12, and 20-24 under 35 U.S.C. 103 is withdrawn in view of claim amendment.
The rejection of claims 1-2, 10-12, and 20-24 under nonstatutory double patenting is withdrawn in view of claim amendment.
Claim Interpretation
Regarding instant claim 1, the step a) “obtaining one or more tissue samples from one or more biopsies and/or surgical resections of a tumor in a subject, without fragmentation” is interpreted as the tissue samples not undergoing further sectioning or fragmentation of the tissue samples obtained in step a) while step b) allows for digestion of the of the tissue sample as indicated in the specification page 10, paragraph 19 and page 17, paragraph 46.
New Claim Rejections Necessitated by Amendment
Claim Rejections – 35 USC § 112(b)
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.
Claim 25-26 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.
Regarding claim 25, the Markush grouping has the word “and” listed two times in lines 5 and 8, wherein line 5 isn’t grouping a single genus of species. It’s unclear if the species that follow epithelial cancer in line 5 are part of the group. Thus, the metes and bounds of the Markush grouping are unclear. While it is appropriate to list “and” as part of a genus of species grouping of “squamous cell carcinomas of the mouth, throat, larynx, and lung” in line 4, extraneous “and” groupings are an improper Markush format. Claim 26 further includes the improper format of claim 25.
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.
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.
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.
Claims 1-2, 10-12, 20-21, and 25-26 are rejected under 35 U.S.C. 103 as being unpatentable over US 20180282694 (Wardell S et al. effective filing date 3/29/2017 reference of record), US 20190276802 (Simpson-Abelson MR et al. effective filing date 11/17/2016 reference of record), Panelli MC et al. (J Immunol 2000 164 (1), 495–504 reference of record), and Ullenhag et al. (Cancer Immunol Immunother. 2011 61(5):725–732. reference of record).
Regarding instant claims 1, and 10-13 Wardell taught a method comprising rapid expansion (REP) of a tumor infiltrating lymphocytes (TIL) population for use in adoptive cell therapy, wherein the method comprises:
culturing and performing an expansion of the TILs directly from a bulk, non-purified tumor fragment from a subject in a culture medium comprising IL-2 in an amount effective to expand TILs with enriched tumor-reactivity, wherein the bulk, non-purified tumor comprises a surgical tumor resection obtained from the subject for 11 days,
culturing the cells with a Rapid Expansion Protocol (REP), wherein TIL are cultured with feeders and OKT3 for REP expansion for an additional 11 days;
harvesting the TIL;
administering the TIL to the subject with the tumor
(page 8, paragraph 195 and FIG. 68).
PNG
media_image1.png
402
917
media_image1.png
Greyscale
Regarding instant claims 1 and 13, Wardell taught TILs can be initially cultured from enzymatic tumor digests and tumor fragments obtained from patients (page 18, paragraph 323). Regarding instant claims 1 and 13, Wardell taught fragmentation is by digestion (page 18, paragraph 323). Regarding instant claims 1 and 13, Wardell taught a patient tumor sample may be a surgical resection or needle biopsy, wherein the sample contains a mixture of tumor and TIL cells (page 17, paragraph 318). Regarding instant claims 1 and 13, Wardell taught the tumor digests are incubated in 2 mL wells in media comprising inactivated human AB serum with IL-2 (page 18, paragraph 323), which would be a complete media. Wardell taught culture of TILs in a complete culture medium containing IL-2 was effective for expanding TILs (page 78, paragraph 1628-1630). Regarding instant claim 2, Wardell taught tumor digestion with an enzyme media that comprised collagenase (page 18, paragraph 326). Wardell taught Adoptive T-cell therapy with autologous tumor infiltrating lymphocytes (TIL) demonstrated clinical efficacy in patients with metastatic melanoma and other tumors (page 114, paragraph 2385). Regarding instant claims 20-24, Wardell taught the solid tumor may be of any cancer type (page 17, paragraph 318) including a sarcoma (page 15, paragraph 295). Regarding instant claims 25-26, Wardell taught TILs that have undergone an REP procedure have produced successful adoptive cell therapy in patients with melanoma (page 1, paragraph 3) and that administration of TILs manufactured using a process with 11 day Pre-REP with a culture medium comprising IL-2 and 11 day REP was clinically effective in melanoma patients (page 119, paragraph 2462 and Fig. 1).
Wardell did not teach: a) a single embodiment wherein bulk tumors are digested and cultured directly; b) the needle biopsy as a core needle biopsy, but this is obvious in view of Simpson-Abelson, Panelli, and Ullenhag.
Simpson-Abelson taught TILs may be cultured from enzymatic tumor digests and tumor fragments from sharp dissection (page 19, paragraph 503). Simpson-Abelson taught for enzymatic digestion of solid tumors; tumor specimens were resuspended in enzymatic digestion buffer comprising collagenase followed by rotation (page 21, paragraph 521 and Fig. 2). Rotation of the enzymatic digest is a mechanical disruption of the tumor. Simpson-Abelson taught methods of delivering a therapeutically effective amount of an expanded number of tumor infiltrating lymphocytes obtained from tumor remnants to a patient in need thereof, for the treatment of a cancer (abstract). Simpson-Abelson taught using a MACS TDK enzymatic digest procedure, wherein the digest procedure caused poor yield and viability of rTILs was inferior to a procedure with DCH digest which is a DNase-Collagenase-Hyaluronidase digest (page 34, paragraph 724). Simpson-Abelson taught following digestion with DCH solid material can remain in the cell strainer (page 34, paragraph 722). Simpson-Abelson taught during pre-REP of tumor fragments for TIL expansion, tumor-resident TILs emigrate as emigrating TILs (eTILs) and proliferate (page 34, paragraph 725). Simpson-Abelson taught viable TILs remaining in the tumor remnants (rTILs) following the pre-REP were investigated after digestion (page 34, paragraph 725), wherein enzymes are used (page 33, paragraph 719) and rTILs within digested bulk tumor are consistently phenotypically distinct from eTILs (page 34, paragraph 725), and rTILs in the digested tumor were identified to have desirable properties wherein A) rTILs are less terminally differentiated than eTILs (i.e., less likely to die) (pages 34-35, paragraph 728); B) rTIL have lower expression of “exhaustion markers” (LAG3 and TIM3) (page 35, paragraph 729). Simpson-Abelson taught as observed prior to REP, the eTILs and rTILs obtained post-REP were phenotypically distinct, wherein many of the phenotypic differences observed in the pre-REP were preserved during the REP, such as a reduction in LAG3 and TIM3 expression in the rTIL (page 35, paragraph 734 and FIG. 6B). Simpson-Abelson taught the eTIL from either the CD4+ or CD8+ population in melanoma and renal, colorectal, breast, and lung cancer tumors demonstrated an enhancement in the proliferative capacity upon co-culture with rTIL with anti-CD3 antibody when compared to eTIL alone (page 36, paragraph 744 and Fig 11). Simpson-Abelson taught the diversity of the TCRvβ repertoire is greater in the rTIL than in the eTIL (FIG. 9), wherein about 30-50% of the total CDR3 in the eTIL and rTIL are shared (FIG. 10), demonstrating that a large percentage of the total CDR3's are differentially expressed in the two populations (page 36, paragraph 741).
Panelli taught TIL expansion in bulk tumor biopsies, wherein tumor cells, RBC, and TILs were present in a 24-well plate with a complete culture medium comprising Iscove’s medium and 6000 IU/ml IL-2, wherein CD4+ and CD8+ cells were obtained (page 496, right column, third paragraph and Table 2 legend). Panelli taught biopsy expanded TILs could recognize autologous tumor cells (Fig. 1).
Ullenhag taught a successful method of obtaining tumor-infiltrating lymphocytes (TIL) from a tumor in a patient via a core needle biopsy (abstract). Ullenhag taught needle biopsies obtained with an 18 gauge needle that were 2 cm long (page 726, right column, first paragraph).
Regarding instant claims 1-2 10-12, 20-21, and 25-26, it would have been obvious for a person having ordinary skill in the art to take the method of Wardell for adoptive transfer treatment of a subject with expanded TIL comprising rapid expansion (REP) of a tumor infiltrating lymphocytes (TIL) population for use in adoptive cell therapy, wherein the method comprises:
surgically excising a tumor and culturing and performing an expansion of the TILs directly from a bulk, non-purified tumor fragmented sample from a subject, wherein the tumor is a sarcoma or melanoma, in a complete culture medium comprising IL-2 in an amount effective to expand TILs with enriched tumor-reactivity, wherein the bulk, non-purified tumor comprises a surgical tumor resection obtained from the subject for 11 days,
culturing the cells with a Rapid Expansion Protocol (REP), wherein TIL are cultured with feeders and OKT3 for REP expansion for an additional 11 days;
harvesting the expanded TIL population; and
administering the TIL to the subject with the tumor for treatment;
– and: 1) select a patient tumor sample that is a core needle biopsy as taught by Ullenhag;
2) enzymatically digesting the core needle biopsy samples wherein the enzymatic digestion performs the function of the fragmentation and culture enzymatic tumor digests from the patient sample as taught by Wardell, wherein the enzymatic digestion of solid tumors includes a step of resuspension in enzymatic digestion buffer comprising collagenase and rotation of the digest as taught by Simpson-Abelson,
3) culture the initial tumor digests in 2 mL wells in a complete culture medium comprising IL-2 as taught by Wardell; and
4) culture the sample fragment without previous purification into a purified TIL population as taught by Panelli and Wardell.
This is obvious because TILs from solid tumors are effectively expanded in culture media comprising IL-2 for patients and: 1) Wardell taught a needle biopsy and Ullenhag taught a successful method of obtaining tumor-infiltrating lymphocytes (TIL) from a tumor in a patient via a core needle biopsy; 2)-4) Wardell taught these as embodiments of the method; 2) Simpson-Abelson taught enzymatic digestion of solid tumors includes a step of resuspension in enzymatic digestion buffer and rotation of the digest; and 3-4) Panelli taught TIL expansion in bulk tumor biopsies, wherein tumor cells, RBC, and TILs were present in a 24-well plate with a complete media comprising IL-2, wherein CD4+ and CD8+ cells were obtained and wherein the biopsy expanded TILs could recognize autologous tumor cells. Thus, tumor cells and RBC did not negatively affect TIL expansion.
There is a reasonable expectation of success because: 1) Ullenhag taught a successful method of obtaining tumor-infiltrating lymphocytes (TIL) from a tumor in a patient via a core needle biopsy and TILs have been shown to be successfully expanded wherein the TILs can recognize the tumor cells; 2) collagenase enzymatic digests of bulk tumor samples with resuspension and rotation would culture eTIL and rTIL which are phenotypically distinct, wherein rTIL have desirable properties and the co-culture of eTIL and rTIL promote further eTIL proliferation as taught by Simpson-Abelson; 3) Wardell taught culture of TILs in a complete culture medium containing IL-2 was effective for expanding TILs; and
4) Wardell used a tumor fragment and did not disaggregate and purify the TILs from the tumor for pre-rapid expansion culture. Further, Panelli taught effective TIL expansion in bulk tumor biopsies, wherein tumor cells, RBC, and TILs were present in a 24-well plate with a complete culture medium comprising IL-2, wherein CD4+ and CD8+ cells were obtained and wherein the biopsy expanded TILs could recognize autologous tumor cells.
This would produce a method for adoptive transfer treatment of a subject with expanded TIL comprising rapid expansion (REP) of a tumor infiltrating lymphocytes (TIL) population for use in adoptive cell therapy, wherein the method is for the treatment of a solid tumor (instant claim 20) of sarcoma (instant claim 21) or melanoma (instant claim 25-26) comprising:
obtaining a core needle biopsy of a sarcoma or melanoma tumor from a subject;
enzymatically digesting the core needle biopsy sarcoma or melanoma tumor in enzymatic digestion buffer comprising collagenase (instant claim 2) wherein the enzymatic digest performs the function of fragmentation without previous fragmentation or purification of a TIL population;
culturing and performing an expansion of the TILs directly from a bulk, non-purified digested tumor sample from the subject in a complete culture medium comprising IL-2 in an amount effective to expand TILs with enriched tumor-reactivity for 11 days;
culturing the cells with a Rapid Expansion Protocol (REP), wherein TIL are cultured with feeders and OKT3 for REP expansion for an additional 11 days;
harvesting the expanded TIL population (instant claim 10); and
administering the rapidly expanded TIL to the subject for adoptive transfer for treatment of the tumor (instant claim 12).
This method would naturally produce an expanded population of TILs with enriched tumor specificity with an increased TCRvβ repertoire, wherein the period of time IL-2 is cultured with the TILs is 22 days, which is less than 5 weeks (instant claim 11). This further meets the claim limitations of instant claim 1.
Response to Arguments
Independent claim 1 has been amended.
The updated rejection is above.
Applicant argues the combination of Wardell, Simpson-Abelson, Panelli, and Ullenhag must still be able to account for all the limitations of the claims otherwise a single reference teaching a single aspect of a claim without further disclosure or knowledge in the art would be able to render a claim obvious and subsequently render all innovation moot. Applicant asserts that it is this important consideration that has not been met with respect to the present claims. In fact, none of the art cited alone, or in combination with or without the general knowledge of the art at the time the application was filed, can account for all the limitations of Claim 1, let alone claims 2, and 10-12 which are dependent thereon.
Applicant argues the Office alleges that Wardell teaches a method comprising rapid expansion (REP) of tumor infiltrating lymphocytes (TILs) for use in adoptive cell therapy, as allegedly shown in page 8, paragraph 195 and FIG. 68 of Wardell. Wardell also allegedly teaches TILs can be initially cultured from enzymatic tumor digests and tumor fragments obtained from patients, that the patient tumor sample may be a surgical resection or needle biopsy, wherein the sample contains a mixture of tumor and TIL cells, and that adoptive T cell therapy with autologous TILs have demonstrated clinical efficacy in patients with metastatic melanoma and other tumors. The Office acknowledges that Wardell does not teach bulk tumors are digested and cultured directly. However, the Office relies on Simpson-Abelson, Panelli, and Ullenhag. Simpson-Abelson allegedly teaches that TILs may be cultured from enzymatic tumor digests and tumor fragments from sharp digestion and that a MACS TDK enzymatic digest procedure caused poor yield and viability of rTILs being inferior to a DCH digest procedure. Panelli allegedly teaches TIL expansion in bulk tumor biopsies, wherein tumor cells, red blood cells (RBCs), and TILs were present in a 24-well plate with a complete medium, and that biopsy expanded TILs could recognize autologous tumor cells. Ullenhag allegedly teaches a method of obtaining TILs from a tumor via a core needle biopsy, plus specific parameters of the used needle. Thus, the Office alleges that it would have been obvious to one of ordinary skill in the art to combine the method of rapid expansion (REP) of tumor infiltrating lymphocytes (TILs) for use in adoptive cell therapy as taught by Wardell with the methods of Simpson and Panelli to culture the tumor sample, which may be obtained as taught by Ullenhag, without disaggregation and to expand TILs in bulk tumor biopsies, respectively. Applicant respectfully traverses the rejection.
Without agreeing to the assertions of the Office, Applicant has amended claim 1 to recite that no fragmentation is performed in the claimed step (a) (i.e., obtaining tissue sample(s) for enzymatic digestion). Wardell claims a method for expanding TILs, involving "processing a tumor sample obtained from the patient into multiple tumor fragments" prior to the expansion steps (see its claims 1 and 45), or using "processed tumor fragments from a tumor resected from a patient" for TIL expansion (See, Wardell claim 62). Wardell also discloses that "[o]nce obtained, the tumor sample is generally fragmented using sharp dissection into small pieces of between 1 to about 8 mm3 , with from about 2-3 mm3 being particularly useful. The TILs are cultured from these fragments using enzymatic tumor digests." (See, Wardell paragraph [0321]). Such fragmentation steps are also disclosed (expressly or indicatively) in at least Figures 1, 2, 6, l lA, 27, 28A, and 68 (which was cited by the Office, bearing no legends) of Wardell. By contrast, the presently claimed invention removes such fragmentation step prior to enzymatic digestion. As taught by the presently claimed invention, such step, usually including culturing each fragment in a separate well of culture plates, increases the culture method complexity/costs/time and yields dramatically different TIL cultures with different degrees of efficacy against tumor (See, paragraphs [0036] and [0037] of US20220002673Al). In the Examples section (e.g., paragraphs [0075]-[0081]), a conventional fragment-based TIL expansion process (i.e., by mincing a primary tumor tissue specimen into fragments for expansion) is compared with the presently claimed method using a bulk, non-purified tumor digest without fragmentation (i.e., digesting the same tumor tissues using collagenase enzymes and mechanical disruption for expansion). As the result, the presently claimed method results in no significant differences "in terms of total number and phenotypic representation" of the expanded TILs, while having a higher probability of tumor-specific reactivity, compared to the fragment-based TIL expansion method. Thus, the presently claimed invention is patentable over Wardell.
Applicant argues such deficiency cannot be cured by Simpson-Abelson, Panelli, and Ullenhag. SimpsonAbelson claims a method for preparing remnant TILs (rTILs) including a separate step of fragmentating the tumor tissue (See, Simpson-Abelson claim I). Simpson-Abelson further discloses cutting the obtained tumor "into fragments or morcellate the tumor" prior to enzymatic digestion, e.g., using DNase-Collagenase-Hyaluronidase (DCH) methods (See, Simpson-Abelson paragraph [0721] and FIGs. 2 and 7). Thus, Simpson-Abelson, alone or in combination, does not render the presently claimed invention unpatentable.
Applicant argues Panelli discloses a method of expanding TILs from fine needle aspirates (FNA) (See, Panelli Abstract). As disclosed in the section of “Expansion of TIL from FNA" in the right column of its page 496, Panelli discloses that a fine needle (23-gauge) was used to aspirate cells (a mixture of tumor cells, RBCs, and TILs) from metastases for TIL expansion. While not specifying whether any tissue samples can or were obtained using such fine needle, Panelli discloses that "[t]he FNA technique does not permanently affect the architecture of the aspirated lesion because it is characterized by minimal disruption of tissue ( citation omitted)" (See, Panelli, the section under Discussion in the left column of its page 502). Therefore, a skilled artisan may have understood that fragmentation of tumor sample is unnecessary in Panelli only because very little, or none, tissue structures are obtained by the FNA method. Such skilled artisan would not have been motivated to combine the disclosures in Panelli with those in either Wardell or Simpson-Abelson, both of which disclose sufficient amounts of tumor tissue samples are taken and, thus, fragmentation of such tissue samples may be necessary.
Applicant argues Ullenhag discloses a method for expanding TILs from tumor material obtained by ultrasound-guided core needle biopsy or surgery from melanoma patients (See, Ullenhag Abstract). As disclosed in the section titled as "Isolation and characterization of TIL" in the right column on page 726, Ullenhag discloses that core needle biopsies were cut to 0.1-cm-long pieces for TIL expansion. Thus, a skilled artisan reading Ullenhag would not have been motivated to omit the fragmentation step prior to enzymatic digestion.
In response, Applicant's arguments filed 7/23/2026 have been fully considered but they are not persuasive. Regarding the Office acknowledges that Wardell does not teach bulk tumors are digested and cultured directly, the Examiner acknowledges Wardell did not teach: a) a single embodiment wherein bulk tumors are digested and cultured directly. Wardell taught TILs can be initially cultured from enzymatic tumor digests and tumor fragments obtained from patients (page 18, paragraph 323). Wardell taught fragmentation is by digestion (page 18, paragraph 323). Thus, the sample can be enzymatically digested wherein the enzymatic digestion performs the function of the fragmentation for culture of enzymatic tumor digests from the sample.
Regarding Wardell and tumor fragments and fragmentation, as described above, Wardell taught TILs can be initially cultured from enzymatic tumor digests and tumor fragments obtained from patients (page 18, paragraph 323). Wardell taught fragmentation is by digestion (page 18, paragraph 323). Thus, the sample can be enzymatically digested wherein the enzymatic digestion performs the function of the fragmentation for culture of enzymatic tumor digests from the sample which meets the limitations of claim 1 in step b). The bulk expansion of tumor biopsies was taught by Panelli above, wherein Panelli taught TIL expansion in bulk tumor biopsies, wherein tumor cells, RBC, and TILs were present in a 24-well plate with a complete culture medium comprising Iscove’s medium and 6000 IU/ml IL-2, wherein CD4+ and CD8+ cells were obtained (page 496, right column, third paragraph and Table 2 legend). Panelli taught biopsy expanded TILs could recognize autologous tumor cells (Fig. 1). Further, Simpson-Abelson taught during pre-REP of tumor fragments for TIL expansion, tumor-resident TILs emigrate as emigrating TILs (eTILs) and proliferate (page 34, paragraph 725). Simpson-Abelson taught viable TILs remaining in the tumor remnants (rTILs) following the pre-REP were investigated after digestion (page 34, paragraph 725), wherein enzymes are used (page 33, paragraph 719) and rTILs within digested bulk tumor are consistently phenotypically distinct from eTILs (page 34, paragraph 725), and rTILs in the digested tumor were identified to have desirable properties wherein: A) rTILs are less terminally differentiated than eTILs (i.e., less likely to die) (pages 34-35, paragraph 728); B) rTIL have lower expression of “exhaustion markers” (LAG3 and TIM3) (page 35, paragraph 729). Simpson-Abelson taught as observed prior to REP, the eTILs and rTILs obtained post-REP were phenotypically distinct, wherein many of the phenotypic differences observed in the pre-REP were preserved during the REP, such as a reduction in LAG3 and TIM3 expression in the rTIL (page 35, paragraph 734 and FIG. 6B). Simpson-Abelson taught the eTIL from either the CD4+ or CD8+ population in melanoma and renal, colorectal, breast, and lung cancer tumors demonstrated an enhancement in the proliferative capacity upon co-culture with rTIL with anti-CD3 antibody when compared to eTIL alone (page 36, paragraph 744 and Fig 11). Simpson-Abelson taught the diversity of the TCRvβ repertoire is greater in the rTIL than in the eTIL (FIG. 9), wherein about 30-50% of the total CDR3 in the eTIL and rTIL are shared (FIG. 10), demonstrating that a large percentage of the total CDR3's are differentially expressed in the two populations (page 36, paragraph 741). Thus, culture of bulk tumor digests are known to be effective and have beneficial properties.
Regarding Simpson-Abelson, Simpson-Abelson taught: 2) the enzymatic digestion of solid tumors includes a step of resuspension in enzymatic digestion buffer comprising collagenase and rotation of the digest. 2) collagenase enzymatic digests of bulk tumor samples with resuspension and rotation would culture eTIL and rTIL which are phenotypically distinct, wherein rTIL have desirable properties and the co-culture of eTIL and rTIL promote further eTIL proliferation as taught by Simpson-Abelson.
Regarding Panelli, the obvious rational above relies on Panelli to 4) culture the sample fragment without previous purification into a purified TIL population. Panelli taught TIL expansion in bulk tumor biopsies, wherein tumor cells, RBC, and TILs were present in a 24-well plate with a complete media comprising IL-2, wherein CD4+ and CD8+ cells were obtained and wherein the biopsy expanded TILs could recognize autologous tumor cells. Thus, tumor cells and RBC did not negatively affect TIL expansion. Further, Panelli taught effective TIL expansion in bulk tumor biopsies, wherein tumor cells, RBC, and TILs were present in a 24-well plate with a complete culture medium comprising IL-2, wherein CD4+ and CD8+ cells were obtained and wherein the biopsy expanded TILs could recognize autologous tumor cells.
Regarding Ullenhag, Ullenhag taught a successful method of obtaining tumor-infiltrating lymphocytes (TIL) from a tumor in a patient via a core needle biopsy (abstract). Thus, it’s obvious to select a patient tumor sample that is a core needle biopsy as taught by Ullenhag.
Claims 1-2, 10-12, 20-21, and 22-26 are rejected under 35 U.S.C. 103 as being unpatentable over US 20180282694 (Wardell S et al. effective filing date 3/29/2017 reference of record), US 20190276802 (Simpson-Abelson MR et al. effective filing date 11/17/2016 reference of record), Panelli MC et al. (J Immunol 2000 164 (1), 495–504 reference of record), and Ullenhag et al. (Cancer Immunol Immunother. 2011 61(5):725–732. reference of record) as applied to claims 1-2, 10-12, 20-21, and 25-26 above, and further in view of Kamamoto D et al. (J Neurooncol 2018 139, 251–259 reference of record).
Wardell, Simpson-Abelson, Panelli, and Ullenhag are described above.
Wardell does not describe the tumor sample as a solitary fibrous tumor, but this is obvious in view of Kamamoto.
Kamamoto taught CD8 was observed in TILs of 13/16 solitary fibrous tumors (abstract). Kamamoto taught diffuse PD-L1 staining coupled with no or sparse CD8 expression was significantly associated with a shorter time to treatment failure and showed a trend toward shorter metastasis free survival (abstract).
Regarding instant claims 22-24, it would have been obvious for a person having ordinary skill in the art to take the method of Wardell, Simpson-Abelson, Panelli, and Ullenhag, above – and 1) expand TILs from solitary fibrous tumors for adoptive cell treatment of subjects with solitary fibrous tumors.
This is obvious because: 1) CD8 was observed in TILs of 13/16 solitary fibrous tumors; and lack of TILs in the tumor showed worst outcomes.
There is a reasonable expectation of success because: 1) TILs are present in solitary fibrous tumors and can be expanded; and 2) outcomes are poor when CD8 TILs are not in the tumor so increasing the TILs by adoptive transfer would be thought to be beneficial.
Response to Arguments
Independent claim 1 has been amended.
The updated rejection is above.
Applicant argues none of the art cited alone, or in combination with or without the general knowledge of the art at the time the application was filed, can account for all
the limitations of Claim 1, let alone claims 2, 10-13, and 20-24, which are dependent thereon.
In response, Applicant's arguments filed 7/23/2026 have been fully considered but they are not persuasive. The discussion of claim 1 is above. The obvious rational is above regarding the amended claims.
Applicant argues Kamamoto discloses detection of expression of biomarkers (e.g., CD3 and CD8) on TILs in patients by immunohistochemistry to determine if correlation with prognosis exists (See, Kamamoto Abstract). Applicant asserts that Kamamoto does not remedy the deficiencies of Wardell, Simpson-Abelson, Panelli, Ullenhag, and Petit. Further, a skilled artisan reading Kamamoto, either alone or in combination with other cited references, would not have been motivated to expand TILs from a tumor tissue sample, without a fragmentation step prior to enzymatic digestion of the tumor tissue sample. Thus, the presently claimed invention is patentable over Wardell, SimpsonAbelson, Panelli, Ullenhag, Petit, and Kamamoto, either alone or in combination.
In response, Applicant's arguments filed 7/23/2026 have been fully considered but they are not persuasive. Kamamoto taught CD8 was observed in TILs of 13/16 solitary fibrous tumors (abstract). Kamamoto taught diffuse PD-L1 staining coupled with no or sparse CD8 expression was significantly associated with a shorter time to treatment failure and showed a trend toward shorter metastasis free survival (abstract).
As indicated in the obvious rational above, it would have been obvious for a person having ordinary skill in the art to take the method of Wardell, Simpson-Abelson, Panelli, and Ullenhag, above – and 1) expand TILs from solitary fibrous tumors for adoptive cell treatment of subjects with solitary fibrous tumors. This is obvious because: 1) CD8 was observed in TILs of 13/16 solitary fibrous tumors; and lack of TILs in the tumor showed worst outcomes. There is a reasonable expectation of success because: 1) TILs are present in solitary fibrous tumors and can be expanded; and 2) outcomes are poor when CD8 TILs are not in the tumor so increasing the TILs by adoptive transfer would be thought to be beneficial.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 10-12, and 20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6-16, and 19-24 of copending Application No. 18/555,584 in view of copending Application No. 18/555,584.
Regarding instant claims 1-2, copending claim 1 taught a method of producing an expanded tumor reactive tumor infiltrating lymphocytes (TIL) population for use in adoptive cell therapy comprising: (a) obtaining a bulk, non-purified tumor digest from one or more tissue samples, wherein the one or more tissue samples comprise one or more core biopsies: (b) digesting the bulk, non- purified tumor digest with a human or humanized enzyme comprising collagenase; and (c) culturing the bulk, non-purified tumor digest in a culture medium comprising IL-2 in an amount effective to expand tumor-infiltrating lymphocytes with enriched tumor-reactivity, wherein the one or more tissue samples comprise performing obtaining one or more core biopsies before digesting the one or more core biopsies in copending claims 6-7, wherein the tissue samples are digested without disaggregating the specimen in copending claim 10. Regarding instant claim 10, copending claim 12 taught harvesting the expanded TIL population. Regarding instant claim 11, copending claim 13 taught culturing the TIL population in IL-2 comprising complete culture media for 5 weeks or less. Regarding instant claim 12, copending claim 14 taught administering the rapidly expanded TIL population and administering the TIL population to a subject. Regarding instant claim 20, copending claim 24 taught the tumor as a solid tumor.
The claims of ‘584 did not teach a single embodiment of the claimed method wherein: 1) the tissue samples are digested without disaggregating the specimen; 2) culturing the TIL population in IL-2 comprising culture medium for 5 weeks or less; 3) harvesting the expanded TIL population; 4) administering the rapidly expanded TIL population and administering the TIL population to a subject; 5) performing the core needle biopsy on a solid tumor, but this is obvious in view of the copending claims.
Regarding instant claims 1-2, 10-12, and 20, it would have been obvious for a person having ordinary skill in the art to take the method of copending claims 1, 6-7, comprising a method of producing an expanded tumor reactive tumor infiltrating lymphocytes (TIL) population for use in adoptive cell therapy comprising: (a) obtaining a bulk, non-purified tumor digest from one or more tissue samples, wherein the one or more tissue samples comprise one or more core biopsies: (b) digesting the bulk, non- purified tumor digest with a human or humanized enzyme comprising collagenase; and (c) culturing the bulk, non-purified tumor digest in a culture medium comprising IL-2 in an amount effective to expand tumor-infiltrating lymphocytes with enriched tumor-reactivity, wherein the one or more tissue samples comprise performing obtaining one or more core biopsies before digesting the one or more core biopsies – and modify the method to include:
1) wherein the tissue samples are digested without disaggregating the specimen as taught by copending claim 10; 2) culturing the TIL population in IL-2 comprising complete culture medium for 5 weeks or less as taught by copending claim 13; 3) harvesting the expanded TIL population as taught by copending claim 12; 4) administer the rapidly expanded TIL population and administering the TIL population to a subject as taught by copending claim 14; 5) perform the core needle biopsy on a solid tumor as taught by copending claim 24.
This is obvious because: 1) copending claim 10 taught tissue samples could be digested without disaggregation; 2) copending claim 12 taught harvesting the expanded TIL population; 2) copending claim 13 taught culturing the TIL population in IL-2 comprising complete culture media for 5 weeks or less; 3) copending claim 14 taught administering the rapidly expanded TIL population and administering the TIL population to a subject; 4) copending claim 24 taught the tumor as a solid tumor.
There is a reasonable expectation of success because: 1) copending claim 10 taught tissue samples could be digested without disaggregation; 2) and 4) the TILs have enriched tumor-reactivity and would need to be harvested and administered for treatment; 3) The TILs are already known to be cultured in IL-2 comprising complete culture medium and copending claim 13 teaches the timing of the culture for enriched tumor-reactivity; and 5) solid tumors are known to have TILs.
This would produce a method comprising producing an expanded tumor reactive infiltrating lymphocyte population in a complete culture medium comprising IL-2 for use in adoptive cell therapy, wherein collagenase digestion (instant claim 2) is performed on one or more core biopsy samples, and wherein one or more core biopsies from a solid tumor (instant claim 20) are digested without disaggregating the specimen, wherein culturing the TIL population in IL-2 comprising complete culture medium for 5 weeks or less , which is rapid (instant claim 11), wherein the TIL are harvested from the expanded TIL population (instant claim 10), wherein the rapidly expanded TIL population harvested is administered to a subject (instant claim 12)(instant claim 1). This method would naturally produce expanded TILs with enriched tumor specificity.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Independent claim 1 has been amended.
The updated rejection is above.
Claims 1-2, 10-12, and 20-24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6-16, and 19-24 of copending Application No. 18/555,584 in view of copending Application No. 18/555,584 in view of Kamamoto D et al. (J Neurooncol 2018 139, 251–259 reference of record).
The claims of the copending ‘584 teach the limitations of claims 1-2, 10-13, and 20 for the reasons set forth above.
The claims of ‘584 did not teach: 1) the cancer is a solitary fibrous tumor, but this is obvious in view of Kamamoto.
Kamamoto taught CD8 was observed in TILs of 13/16 solitary fibrous tumors (abstract). Kamamoto taught diffuse PD-L1 staining coupled with no or sparse CD8 expression was significantly associated with a shorter time to treatment failure and showed a trend toward shorter metastasis free survival (abstract).
Regarding instant claims 21-24, it would have been obvious for a person having ordinary skill in the art to take the method of copending claims 1, 6-7, 10, 12-14, and 24 of ‘584 above
– and 1) expand TILs from solitary fibrous tumors for adoptive cell treatment of subjects with solitary fibrous tumors.
This is obvious because: 1) CD8 was observed in TILs of 13/16 solitary fibrous tumors; and lack of TILs in the tumor showed worst outcomes.
There is a reasonable expectation of success because: 1) TILs are present in solitary fibrous tumors and can be expanded; and 2) outcomes are poor when CD8 TILs are not in the tumor so increasing the TILs by adoptive transfer would be thought to be beneficial.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Independent claim 1 has been amended.
The updated rejection is above.
Claims 1-2, 10-12, and 25-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6-16, and 19-24 of copending Application No. 18/555,584 in view of copending Application No. 18/555,584 in view of US 20180282694 (Wardell S et al. effective filing date 3/29/2017 reference of record).
The claims of the copending ‘584 teach the limitations of claims 1-2, 10-13, and 20 for the reasons set forth above.
The claims of ‘584 did not teach: 1) the cancer is melanoma in view of Wardell.
Regarding instant claims 1, and 10-13 Wardell taught a method comprising rapid expansion (REP) of a tumor infiltrating lymphocytes (TIL) population for use in adoptive cell therapy, wherein the method comprises:
culturing and performing an expansion of the TILs directly from a bulk, non-purified tumor fragment from a subject in a culture medium comprising IL-2 in an amount effective to expand TILs with enriched tumor-reactivity, wherein the bulk, non-purified tumor comprises a surgical tumor resection obtained from the subject for 11 days,
culturing the cells with a Rapid Expansion Protocol (REP), wherein TIL are cultured with feeders and OKT3 for REP expansion for an additional 11 days;
harvesting the TIL;
administering the TIL to the subject with the tumor
(page 8, paragraph 195 and FIG. 68).
PNG
media_image1.png
402
917
media_image1.png
Greyscale
Regarding instant claims 1 and 13, Wardell taught TILs can be initially cultured from enzymatic tumor digests and tumor fragments obtained from patients (page 18, paragraph 323). Regarding instant claims 1 and 13, Wardell taught fragmentation is by digestion (page 18, paragraph 323). Regarding instant claims 1 and 13, Wardell taught a patient tumor sample may be a surgical resection or needle biopsy, wherein the sample contains a mixture of tumor and TIL cells (page 17, paragraph 318). Regarding instant claims 1 and 13, Wardell taught the tumor digests are incubated in 2 mL wells in media comprising inactivated human AB serum with IL-2 (page 18, paragraph 323), which would be a complete media. Wardell taught culture of TILs in a complete culture medium containing IL-2 was effective for expanding TILs (page 78, paragraph 1628-1630). Regarding instant claim 2, Wardell taught tumor digestion with an enzyme media that comprised collagenase (page 18, paragraph 326)
Wardell taught Adoptive T-cell therapy with autologous tumor infiltrating lymphocytes (TIL) demonstrated clinical efficacy in patients with metastatic melanoma and other tumors (page 114, paragraph 2385). Regarding instant claims 20-24, Wardell taught the solid tumor may be of any cancer type (page 17, paragraph 318) including a sarcoma (page 15, paragraph 295). Regarding instant claims 25-26, Wardell taught TILs that have undergone an REP procedure have produced successful adoptive cell therapy in patients with melanoma (page 1, paragraph 3) and that administration of TILs manufactured using a process with 11 day Pre-REP with a culture medium comprising IL-2 and 11 day REP was clinically effective in melanoma patients (page 119, paragraph 2462 and Fig. 1).
Regarding instant claims 25-26, it would have been obvious for a person having ordinary skill in the art to take the method of copending claims 1, 6-7, 10, 12-14, and 24 of ‘584 above
– and 1) expand TILs from a melanoma tumor for adoptive cell treatment of subjects with melanoma.
This is obvious because: 1) Wardell taught TILs that have undergone a REP procedure have produced successful adoptive cell therapy in patients with melanoma and that administration of TILs manufactured using a process with 11 day Pre-REP with a culture medium comprising IL-2 and 11 day REP was clinically effective in melanoma patients.
There is a reasonable expectation of success because: 1a) TILs are present in melanoma tumors and can be expanded; and 2) adoptive transfer of TILs is clinically effective for melanoma.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Independent claim 1 has been amended.
The updated rejection is above.
Claims 1-2, 10-13, and 20-24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 6-7, 10-15, and 24-28 of copending Application No. 18/842,179.
Regarding instant claims 1-2, copending claim 1 taught a method of producing an expanded tumor reactive tumor infiltrating lymphocytes (TIL) population for use in adoptive cell therapy comprising: (a) obtaining one or more tissue samples from a subject; b) digesting the one or more tissue samples with a collagenase enzyme; c) culturing bulk non-purified tumor digest from a human subject in a culture medium comprising IL-2 in an amount effective to expand tumor-infiltrating lymphocytes with enriched tumor-reactivity, wherein the one or more tissue samples comprise performing obtaining one or more core biopsies before digesting the one or more core biopsies in copending claims 6-7, wherein the tissue samples are digested without disaggregating the specimen in copending claim 10. Regarding instant claim 10, copending claim 12 taught harvesting the expanded TIL population. Regarding instant claim 11, copending claim 13 taught culturing the TIL population in IL-2 comprising complete culture media for 5 weeks or less. Regarding instant claim 12, copending claim 14 taught administering the rapidly expanded TIL population and administering the TIL population to a subject. Regarding instant claim 20, copending claim 24 taught the tumor as a solid tumor. Regarding instant claim 21-24, copending claim 28 taught the tumor as a solitary fibrous tumor.
The claims of ‘179 did not teach a single embodiment of the claimed method wherein: 1) the tissue samples are digested without disaggregating the specimen; 2) culturing the TIL population in IL-2 comprising culture medium for 5 weeks or less; 3) harvesting the expanded TIL population; 4) administering the rapidly expanded TIL population and administering the TIL population to a subject; 5) performing the core needle biopsy on a solid tumor, but this is obvious in view of the copending claims.
Regarding instant claims 1-2, 10-12, and 20-24, it would have been obvious for a person having ordinary skill in the art to take the method of copending claims 1 and 6-7, comprising a method of producing an expanded tumor reactive tumor infiltrating lymphocytes (TIL) population for use in adoptive cell therapy comprising: (a) obtaining a bulk, non-purified tumor digest from one or more tissue samples, wherein the one or more tissue samples comprise one or more core biopsies: (b) digesting the bulk, non- purified tumor digest with a human or humanized enzyme comprising collagenase; and (c) culturing the bulk, non-purified tumor digest in a culture medium comprising IL-2 in an amount effective to expand tumor-infiltrating lymphocytes with enriched tumor-reactivity, wherein the one or more tissue samples comprise performing obtaining one or more core biopsies before digesting the one or more core biopsies – and modify the method to include:
1) wherein the tissue samples are digested without disaggregating the specimen as taught by copending claim 10; 2) culturing the TIL population in IL-2 comprising complete culture medium for 5 weeks or less as taught by copending claim 13; 3) harvesting the expanded TIL population as taught by copending claim 12; 4) administer the rapidly expanded TIL population and administering the TIL population to a subject as taught by copending claim 14; 5) perform the core needle biopsy on a solid tumor as taught by copending claim 24.
This is obvious because: 1) copending claim 10 taught tissue samples could be digested without disaggregation; 2) copending claim 12 taught harvesting the expanded TIL population; 2) copending claim 13 taught culturing the TIL population in IL-2 comprising complete culture media for 5 weeks or less; 3) copending claim 14 taught administering the rapidly expanded TIL population and administering the TIL population to a subject; 4) copending claim 24 taught the tumor as a solid tumor.
There is a reasonable expectation of success because: 1) copending claim 10 taught tissue samples could be digested without disaggregation; 2) and 4) the TILs have enriched tumor-reactivity and would need to be harvested and administered for treatment; 3) The TILs are already known to be cultured in IL-2 comprising complete culture medium and copending claim 13 teaches the timing of the culture for enriched tumor-reactivity; and 5) solid tumors are known to have TILs.
This would produce a method comprising producing an expanded tumor reactive infiltrating lymphocyte population in a complete culture medium comprising IL-2 for use in adoptive cell therapy, wherein collagenase digestion (instant claim 2) is performed on one or more core biopsy samples, and wherein one or more core biopsies from a solid solitary fibrous tumor (instant claims 20-24) are digested without disaggregating the specimen, wherein culturing the TIL population in IL-2 comprising complete culture medium for 5 weeks or less , which is rapid (instant claim 11), wherein the TIL are harvested from the expanded TIL population (instant claim 10), wherein the rapidly expanded TIL population harvested is administered to a subject (instant claim 12)(instant claim 1). This method would naturally produce expanded TILs with enriched tumor specificity.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Independent claim 1 has been amended.
The updated rejection is above.
Claims 1-2, 10-13, and 20-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 6-7, 10-15, and 24-28 of copending Application No. 18/842,179 in view of US 20180282694 (Wardell S et al. effective filing date 3/29/2017 reference of record).
The claims of the copending ‘179 teach the limitations of claims 1-2, 10-13, and 20-24 for the reasons set forth above.
The claims of ‘179 did not teach: 1) the cancer is melanoma in view of Wardell.
Regarding instant claims 1, and 10-13 Wardell taught a method comprising rapid expansion (REP) of a tumor infiltrating lymphocytes (TIL) population for use in adoptive cell therapy, wherein the method comprises:
culturing and performing an expansion of the TILs directly from a bulk, non-purified tumor fragment from a subject in a culture medium comprising IL-2 in an amount effective to expand TILs with enriched tumor-reactivity, wherein the bulk, non-purified tumor comprises a surgical tumor resection obtained from the subject for 11 days,
culturing the cells with a Rapid Expansion Protocol (REP), wherein TIL are cultured with feeders and OKT3 for REP expansion for an additional 11 days;
harvesting the TIL;
administering the TIL to the subject with the tumor
(page 8, paragraph 195 and FIG. 68).
PNG
media_image1.png
402
917
media_image1.png
Greyscale
Regarding instant claims 1 and 13, Wardell taught TILs can be initially cultured from enzymatic tumor digests and tumor fragments obtained from patients (page 18, paragraph 323). Regarding instant claims 1 and 13, Wardell taught fragmentation is by digestion (page 18, paragraph 323). Regarding instant claims 1 and 13, Wardell taught a patient tumor sample may be a surgical resection or needle biopsy, wherein the sample contains a mixture of tumor and TIL cells (page 17, paragraph 318). Regarding instant claims 1 and 13, Wardell taught the tumor digests are incubated in 2 mL wells in media comprising inactivated human AB serum with IL-2 (page 18, paragraph 323), which would be a complete media. Wardell taught culture of TILs in a complete culture medium containing IL-2 was effective for expanding TILs (page 78, paragraph 1628-1630). Regarding instant claim 2, Wardell taught tumor digestion with an enzyme media that comprised collagenase (page 18, paragraph 326)
Wardell taught Adoptive T-cell therapy with autologous tumor infiltrating lymphocytes (TIL) demonstrated clinical efficacy in patients with metastatic melanoma and other tumors (page 114, paragraph 2385). Regarding instant claims 20-24, Wardell taught the solid tumor may be of any cancer type (page 17, paragraph 318) including a sarcoma (page 15, paragraph 295). Regarding instant claims 25-26, Wardell taught TILs that have undergone an REP procedure have produced successful adoptive cell therapy in patients with melanoma (page 1, paragraph 3) and that administration of TILs manufactured using a process with 11 day Pre-REP with a culture medium comprising IL-2 and 11 day REP was clinically effective in melanoma patients (page 119, paragraph 2462 and Fig. 1).
Regarding instant claims 25-26, it would have been obvious for a person having ordinary skill in the art to take the method of copending claims 1, 6-7, 10, 12-14, and 28 of ‘179 above
– and 1) expand TILs from a melanoma tumor for adoptive cell treatment of subjects with melanoma.
This is obvious because: 1) Wardell taught TILs that have undergone a REP procedure have produced successful adoptive cell therapy in patients with melanoma and that administration of TILs manufactured using a process with 11 day Pre-REP with a culture medium comprising IL-2 and 11 day REP was clinically effective in melanoma patients.
There is a reasonable expectation of success because: 1a) TILs are present in melanoma tumors and can be expanded; and 2) adoptive transfer of TILs is clinically effective for melanoma.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Independent claim 1 has been amended.
The updated rejection is above.
Conclusion
No claims are allowable.
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 JOHN J SKOKO III whose telephone number is (571)272-1107. The examiner can normally be reached M-F 8:30 - 5:00.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Z Wu can be reached on (571)272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/J.J.S./Examiner, Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643
