DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendments
Applicant's amendments filed 6/22/2026 to claims 3, 143-146, 165, 166, 170, 196-201, and 204-206 have been entered. Claims 1, 2, 4, 9-142, 147-164, and 171-195 are canceled. Claims 3, 5-8, 143-146, 165-170, and 197-206 remain pending and are being considered on their merits. No claims are withdrawn from consideration at this time. References not included with this Office action can be found in a prior action.
The instant claim amendments have overcome the 35 U.S.C. § 112(b) rejections of record, which are withdrawn.
Any other rejections of record not particularly addressed below are withdrawn in light of the claim amendments and/or applicant’s comments.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 3, 5-7, 143-146, 165-169, 196-201, and 204-206 are rejected under 35 U.S.C. 103 as being unpatentable over Veerapathran (WO 2020/061429; provided in the IDS dated 1/17/2024) in view of Bender et al. (CA 3057975) and Bakhach (Organogenesis (2009), 5(3), 119-126) as evidenced by Daboor et al. (American Journal of Biochemistry and Biotechnology 6 (4): 239-263, 2010).
Veerapathran teaches a method for cryopreserving tumor tissue comprising:(i) placing in a pre-cooled closable vessel comprising cryopreservation medium a tumor digest obtained from digesting in an enzymatic media tumor tissue or tumor fragments produced from fragmenting tumor tissue and closing the vessel;(ii) incubating the closed vessel comprising the tumor digest and cryopreservation medium at a temperature of about 2-8°C for a time period of about 30 to 60 minutes;(iii) slow-freezing the vessel in a controlled-rate freezing device; and(iv) transferring the vessel to a liquid nitrogen freezer (Examples 4 and 5, Fig. 9 and [0057]; also Fig. 1 for a general schematic of the methods), reading in-part on claim 3. Veerapathran teaches adding DNAse and collagenase to the tumor digests ([00438)), reading on claims 5-6 and reading on claim 7 as evidenced by Daboor (see the Abstract of Daboor, e.g. collagenases are operable at a pH range of 6-8 and so are reasonably construed as a “neutral protease). Veerapathran teaches fragmenting the tumor tissue into spherical fragments having a diameter range of 1.5-6 mm ([00308]), reading on claims 143 and 144. Veerapathran teaches fragmenting the tumor tissue into rectangular fragments having a shortest edge length of at least 1.5 mm and a longest edge length of about 6 mm ([00309]), reading on claim 145. Veerapathran teaches fragmenting the tumor tissue into cubical fragments having edge lengths of between about 1.5 mm and 6 mm. ([00309]), reading on claim 146. Veerapathran teaches a cryopreservation medium comprising 10% DMSO ([00314], reading on claims 165 and 166. Veerapathran teaches a cryopreservation medium comprising at least 50 µg/ml ([00316]), reading on claims 167 and 168. Veerapathran teaches placing tumor-infiltrating lymphocytes (i.e. TILs) into cryogenic vials and then placing the vials loaded with the cells into a -80°C freezer for 24 hours ([00645]), reading on claims 169 and 199 and reading in-part on claims 200 and 201. Veerapathran teaches cooling rates of -0.5, -1, and -10°C/min and does not teach adding any isopropyl alcohol (e.g. IPA) ([00767] in Example 4), reading on claims 196 and 197. Veerapathran teaches placing an aluminum cassette holder, a plurality of cryostorage cassettes for CS750 freezer bags, and CS750 freezer bags into the controlled rate freezer (Example 4), reading on claim 198. Veerapathran teaches wherein after recovery from freezing, the cells have a post-thaw viability of at least about 80% ([0057], [00919], and Fig. 9, the right panel: 2.12 x 109 cells at 60 min divided by 2.47 x 109 cells Gen2 control equates to 87.8% viability), reading on claim 206.
Regarding claim 3, Veerapathran does not teach pre-cooling the closable vessel. Regarding claims 200 and 201, Veerapathran does not teach freezing at -80°C for 3-5 hours or 4 hours, respectively.
Bender teaches methods of making tumor-infiltrating lymphocytes (TILs) from tumors obtained from a patient and then cryopreserving said TILs ([0005-0007]). Bender teaches placing cryobags into pre-cooled aluminum freezer canisters/cassettes (Example 1, particularly step 19.), reading on claim 3.
Bakhach teaches that in methods of cryopreservation of biological tissues, the overall goal/aim is to avoid thermal shock (p122, left column, paragraph starting “Different tissues and cells…”), wherein “thermal shock” is defined as a brisk change in temperature during cooling even in the absence of ice formation and essentially occurs between 37°C and 15°C and again between 0°C and-80°C (p121, left column, subheading “Thermal Shock”), reading on claim 3.
Regarding claim 3, It would have been obvious to a person of ordinary skill in the art before the invention was filed to further pre-cool the freezer canisters/cassettes of Veerapathran in view of Bender. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because Veerapathran and Bender are both directed towards similar methods of cryopreserving TILs obtained from tumor tissue. The skilled artisan would have been motivated to do so because Bakhach teaches that thermal shock should be avoided in methods of cryopreserving biological tissues, and so the addition of Bender’s pre-cooling step would predictably improve the methods of Veerapathran by reducing the likelihood of thermal shock when placing the CS750 freezer bags into the controlled rate freezer of Veerapathran.
Regarding claims 200 and 201, optimization within prior art conditions or through routine experimentation will generally not support patentability absent a showing of criticality of the claimed range to the contrary. See M.P.E.P. § 2144.05, particularly subsections II and III. In this case, Veerapathran clearly teaches that the freezing time is directly proportional to the applied cooling rate, and that a cooling rate of -1°C/min for 60 minutes is effective to reduce the temperature from -20°C to -80°C and is effective to cryopreserve the TILs obtained from tumor tissue. Thus, the burden is shifted back to establish criticality of the claimed freezing time range by objective evidence.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Veerapathran, Bender, and Bakhach as applied to claim 3 above, and further in view of Terman (US 5,728,388).
The teachings of Veerapathran, Bender, and Bakhach are relied upon as set forth above.
Regarding claim 8, Veerapathran, Bender, and Bakhach do not teach hyaluronidase.
Terman teaches methods of obtaining host cells from tumor-infiltrating lymphocytes (TILs), the method comprising in-part obtaining solid tumors (from subjects) and enzymatically digesting said tumors with a combination of hyaluronidase, DNAse, and collagenase (Example 8), reading on claim 8.
Regarding claim 8, "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted). See M.P.E.P. § 2144.06. In this case, both Veerapathran and Terman are directed towards methods of obtaining TILs from tumor tissue and so adding Terman’s hyaluronidase to Veerapathran for the same purpose of enzymatically digesting tumor tissue would be predictably advantageous.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claim 170 is rejected under 35 U.S.C. 103 as being unpatentable over Veerapathran, Bender, and Bakhach as applied to claim 3 above, and further in view of Wardell et al. (US 2018/0325954) as evidenced by the product information to OriGen CryoStore™ Freezing Bag(s) (2018; of record).
The teachings of Veerapathran, Bender, and Bakhach are relied upon as set forth above.
Regarding claim 8, Veerapathran, Bender, and Bakhach do not teach wherein the closable vessel is filled from about 50% to about 85% volume with cryopreservation medium.
Wardell teaches methods of obtaining tumor-infiltrating lymphocytes from tumors (Abstract and Fig. 1). Wardell teaches loading CS750 (freezer) bags with a final target volume per bag of 100 or 125 ml ([3482]-[3483] and table after [3483]).
The product information to OriGen CryoStore™ Freezing Bag(s) teaches that CS750 freezing bags inherently have a working volume of 80-190 ml (3rd page, “CS750”). Therefore, Wardell’s target fill volumes relative to the maximum working volume of the CS750 freezing bags inherently equates to (100ml/190ml) = 52.6%, (125ml/190ml) = 65.8%, and so reads on the percentage fill volume range of claim 170 as evidenced by the product information to OriGen CryoStore™ Freezing Bag(s) teaches
It would have been obvious to a person of ordinary skill in the art before the invention was filed to further fill the CS750 freezer bags of Veerapathran to either 52.6% or 65.8% fill volume in view of Wardell and as evidenced by the product information to OriGen CryoStore™ Freezing Bag(s). A person of ordinary skill in the art would have had a reasonable expectation of success to do so because Veerapathran and Wardell are both directed towards similar methods of cryopreserving TILs obtained from tumor tissue. The skilled artisan would have been motivated to do so because Wardell teaches that either 52.6% or 65.8% fill volume for filling CS750 freezer bags with TILs would predictably yield CS750 freezer bags loaded with TILs based upon the inherent working volume range of the CS750 freezer bags as evidenced by the product information to OriGen CryoStore™ Freezing Bag(s) in Veerapathran’s methods of making TILs from tumor tissue. See M.P.E.P. § 2143(I)(A).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claims 202 and 203 are rejected under 35 U.S.C. 103 as being unpatentable over Veerapathran, Bender, and Bakhach as applied to claim 3 above, and further in view of Schryver et al. (US 2014/0335614).
The teachings of Veerapathran, Bender, and Bakhach are relied upon as set forth above.
Regarding claim 202, Veerapathran, Bender, and Bakhach do not teach wherein the slow-freezing comprises incubating the controlled-rate freezing device with dry ice. Regarding claim 202, Veerapathran, Bender, and Bakhach do not teach wherein the slow-freezing comprises incubating the controlled-rate freezing device in a -80°C.
Schryver teaches Improved methods for cryopreservation of cells result when cells are cooled at controlled rates in devices that ensure a constant rate of cooling of less than 10° C (Abstract). Schryver teaches utilizing a passive cooling device, such as CoolCell® enables highly consistent, alcohol-free cooling of biological samples and which cools a controlled rate of 1°C/min 2 when the device is placed into a -80°C freezer ([0051]), reading on claim 203. Schryver teaches a -80°C freezer and a dry ice locker as equivalent cooling environments ([0037]), reading on claims 202 and 203. Schryver teaches a sample comprising lymphocytes or tumor samples ([0031]), reading on claims 202 and 203
Regarding claims 202 and 203, it would have been obvious to a person of ordinary skill in the art before the invention was filed to with A person of ordinary skill in the art would have had a reasonable expectation of success in substituting the passive cooling device cooled with either dry ice or placed into a -80°C of Schryver for the controlled rate freezer of Veerapathran because both devices explicitly taught as controlled rate freezers and being useful for THE SAME PURPOSE of cryopreserving mammalian cells and/or tissue. Therefore, these compositions are functional equivalents in the art, and substituting one for the other would have been obvious at the time of the invention. “When a patent ‘simply arranges old elements with each performing the same function it had been known to perform’ and yields no more than one would expect from such an arrangement, the combination is obvious.” See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) at 1395-1396, quoting Sakraida v. AG Pro, Inc., 425 U.S. 273 (1976) and In re Fout, 675 F.2d 297, 301 (CCPA 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious”).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Response to Arguments
Applicant's arguments on pages 6-17 of the reply have been fully considered, but not found persuasive of error for the reasons given below.
On pages 9-10 of the reply, Applicant alleges that the cited portions of Veerapathran are directed towards flash freezing and not the claimed slow-freezing process. This is not found persuasive of error because Example 4 of Veerapathran relies upon the same narrower freezing rates as recited in claim 196 and so are reasonably construed as meeting the broader embodiment of “slow freezing” of claim 3. Furthermore, none of Veerapathran as was and remained cited against the claims makes any recitation of “flash freezing”.
In response to applicant's argument on page 10-12 of the reply that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). In this case, claim 3 only recites a generic “tumor tissue” and generic “tumor digest” and the broadest reasonable interpretation does not exclude the tumor infiltrating lymphocytes obtained from tumor tissue as the narrower embodiment of the generic “tumor tissue” of claim 3 (see M.P.E.P. § 2111).
Applicant’s argument on page 12 of the reply that the claimed freezing times are not routine optimization (presumably referring to claims 200 and 201) is not found persuasive, because Applicant has not cited any evidence in the record to rebut the prima facie case for obviousness of record; see M.P.E.P. § 2144.05(III).
Applicant’s remaining arguments on page 12 of the reply are not persuasive, as they rely on an overly narrow interpretation of the scope of claim 3 that cannot be held as the broadest reasonable interpretation at this time (see M.P.E.P. § 2111). Briefly restated, claim 3 does not yet exclude the tumor infiltrating lymphocytes obtained from tumor tissue of Veerapathran as available prior art.
On pages 12-13 of the reply, Applicants rely on arguments traversing the above rejection of claims 3, 5-7, 143-146, 165-169, 196-201, and 204-206 over Veerapathran in view of Bender and Bakhach to traverse the rejection of claim 8 further in view of Terman, claim 170 further in view of Wardell as evidenced by the product information to Origen Cryostore®. Therefore, the response set forth above to arguments also applies to this rejection.
On pages 13-14 of the reply, Applicant alleges that Schryver is deficient by not teaching every element of claim 3. This is not found persuasive of error as Schryver is not applied alone under 35 U.S.C. § 102 but as a secondary reference with Veerapathran in view of Bender and Bakhach against only dependent claims 202 and 203 under 35 U.S.C. § 103 and the claimed invention becomes prima facie obvious when the references are considered together as a whole rather than each alone. Applicant appears to be alleging it would have been unpredictable to substitute Schryver passive cooling device (CoolCell®) for the controlled rate freezer of Veerapathran in Veerapathran’s methods, but absolute predictability is not a prerequisite for a prima facie case for obviousness (see M.P.E.P. § 2143.02) and Applicant has not asserted any particular technical rationale supported by any preponderance of evidence to support the general allegation of unpredictability.
On pages 14-16 of the reply, Applicant alleges that Example 12 of the specification rebuts the prima facie case for obviousness of record. See M.P.E.P. § 716 as a whole for review of secondary considerations with respect to 35 U.S.C. § 103 rejections. In this case, Applicant has not met the nexus requirement between the merits of the claimed methods and the proffered evidence of secondary considerations (see M.P.E.P. § 716.01(b)) because Example 12 of the specification is not reasonably commensurate to the scope of the claims. The tumor infiltrating lymphocytes obtained from the tumor tissue Veerapathran are not yet excluded from the claims (see M.P.E.P. § 716.02(d)), and so a comparison of slow-freezing to flash-freezing is not the closest prior art comparison at this time as Veerapathran clearly teaches slow freezing of tumor infiltrating lymphocytes obtained from tumor tissue as cited above (see M.P.E.P. § 716.02(e)).
Conclusion
No claims are allowed. No claims are free of the art.
THIS ACTION IS MADE FINAL. 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 SEAN C BARRON whose telephone number is (571)270-5111. The examiner can normally be reached 7:30am-3:30pm EDT/EST (M-F).
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/Sean C. Barron/Primary Examiner, Art Unit 1653
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