DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 1-5 are pending.
Claims 1-5 have been examined on their merits.
Claim Objections
Claim 1 is objected to because of the following informalities: claim 1 uses bullets. However, claims should be a single sentence.
Claim 1 is also objected to because it recites “TIL.” Abbreviated terms should be spelled out in their first instance. Amending the claim to “tumor-infiltrating lymphocytes (TILs)” would be ameliorative.
Claim 1 also recites “106TIL/cm2” which should be “106 TIL/cm2”.
Claim 3 is objected to because of the following informalities: claim 3 uses bullets. However, claims should be a single sentence.
Claim 3 is objected to because it recites “tumor-infiltrated lymphocytes (TIL). This appears to be a literal machine translation from the original language. In English, the term is “tumor-infiltrating lymphocytes”. Additionally, claim 1, if amended as above, would more appropriately recite “tumor-infiltrating lymphocytes (TILs).” Therefore, the term could be abbreviated in claim 3.
Claim 5 is objected to for the following informalities: claim 5 recites a lone dash (second to last line) dash which should be eliminated.
Appropriate correction is required.
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.
Claims 1-5 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the limitation that the searching “preferably” (line 13, p1; line 14, p2). A claim may be rendered indefinite by reference to subjective term (see MPEP 2173.05(b)(IV)). Specifically, the phrase “preferably” is a subjective term which renders the claim indefinite. The phrase "preferably" is not defined by the claim, the specification does not provide a standard for measuring the scope of the term, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
A claim that requires the exercise of subjective judgment without restriction may render the claim indefinite. In re Musgrave, 431 F.2d 882, 893, 167 USPQ 280, 289 (CCPA 1970). Claim scope cannot depend solely on the unrestrained, subjective opinion of a particular individual purported to be practicing the invention. Datamize LLC v. Plumtree Software, Inc., 417 F.3d 1342, 1350, 75 USPQ2d 1801, 1807 (Fed. Cir. 2005)); see also Interval Licensing LLC v. AOL, Inc., 766 F.3d 1364, 1373, 112 USPQ2d 1188 (Fed. Cir. 2014) (holding the claim phrase "unobtrusive manner" indefinite because the specification did not "provide a reasonably clear and exclusive definition, leaving the facially subjective claim language without an objective boundary”).
For example, in Datamize, the invention was directed to a computer interface screen with an "aesthetically pleasing look and feel." Datamize, 417 F.3d at 1344-45. The meaning of the term "aesthetically pleasing" depended solely on the subjective opinion of the person selecting features to be included on the interface screen. Nothing in the intrinsic evidence (e.g., the specification) provided any guidance as to what design choices would result in an "aesthetically pleasing" look and feel. Id. at 1352. The claims were held indefinite because the interface screen may be "aesthetically pleasing" to one user but not to another. Id. at 1350. See also Ex parte Anderson, 21 USPQ2d 1241 (Bd. Pat. App. & Inter. 1991) (the terms "comparable" and "superior" were held to be indefinite in the context of a limitation relating the characteristics of the claimed material to other materials).
During prosecution, the applicant may overcome a rejection by amending the claim to remove the subjective term, or by providing evidence that the meaning of the term can be ascertained by one of ordinary skill in the art when reading the disclosure. However, "[f]or some facially subjective terms, the definiteness requirement is not satisfied by merely offering examples that satisfy the term within the specification." DDR Holdings, LLC v. Hotels.com, L.P., 773 F.3d 1245, 1261, 113 USPQ2d 1097, 1108 (Fed. Cir. 2014).
For compact prosecution, the term has been interpreted as being optional.
Claim 1 also recites the term “suitable” (line 23, p1) which is a subjective term which renders the claim indefinite. The term “suitable” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Specifically, what would be considered “suitable” would be different between two different scientists carrying out the claimed method steps.
For compact prosecution any supplement is considered suitable.
Claim 2 recites the term “appropriately” which is a subjective term which renders the claim indefinite. The term “appropriately” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. What would be considered appropriate supplementation would be different between two different scientists carrying out the claimed method steps.
For compact prosecution any supplement is considered appropriate.
Claim 3 recites the term “appropriately” which is a subjective term which renders the claim indefinite. The term “appropriately” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. What would be considered appropriate supplementation would be different between two different scientists carrying out the claimed method steps.
For compact prosecution any dosage is considered suitable.
Appropriate clarification is required.
Claim Rejections - 35 USC § 112(d)
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.
Claim 2 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 2 does not further limit claim 1. Claim 1 is limited to a “TIL and other T cells”. However, claim 2 broadens the claim to allow for “NK cells (TINK)” or “other cell types” which includes cells that are not TIL and other T cells.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1 and 2 are rejected under 35 U.S.C. 103 as being unpatentable over Hoffmeister et al. (WO2020078498, published 04/23/2020, on IDS 01/02/2024) in view of Diaz-Montero et al. (Cancer Immunology Immunotherapy) and Chacon et al. (PLOS ONE, 2013).
In regards to claim 1, Hoffmeister teaches methods for extracting autologous tumor infiltrating lymphocytes (TILs, autologous T lymphocytes) from tumor tissues (thus, ex vivo) (Abstract; Description, p1, 10). Hoffmeister teaches that these cells are useful for therapeutic applications and transplantation purposes (Description, p5-6) and are hypertoxic to tumor cells (Description, p10). Since the TILs are autologous from tumor tissues and hypertoxic to those tissues, a person of ordinary skill in the art would have recognized that the method is suitable to use as a patient-specific therapeutic for combating tumors.
In a first stage, Hoffmeister teaches that the tissues are cut into small pieces (thus, comminuted), introduced, evenly distributed, and cultured in a closed meander perfusion bioreactor vessel to obtain TILs (claim 1; Description, p2; Example 1, p 7-9; Example 2, p9-10).
In regards to the limitation of “a defined number of cells”, it is noted that the claims do not require culture a specific number of cells, and therefore, this claim has been interpreted as broadly allowing for any amount of cells. As the tissues as taught by Hoffmeister comprise TILs, they contain a defined number of cells.
Hoffmeister teaches that cells grow in culture medium located in the perfusion meander bioreactor (Abstract; claim 1) and are simultaneously activated and expanded (multiplied) (Example 1, p9 Example 2, p9).
Hoffmeister teaches that medium flows through a channel of the bioreactor with an over flow with a Froud number of not greater than (thus, less than) 0.005 and a bottom flow with a Froud number close to (i.e., about) 0 (claim 1).
Hoffmeister teaches that the medium has directed laminar flow over sedimented cells, which prevents cell stress, which causes rapid growth (expansion) of cells and separation from tissues (Claim 1; Culture medium, p8; Example 1, p8; Example 2, p10).
Hoffmeister teaches that following this step, cells are harvested, centrifuged, and resuspended in a freezing medium in vials (Description, p6; Example 1, p9). Continuing, Hoffmeister teaches that cells are aliquoted and cryopreserved (Description, p6; Example 1, p9).
In a second stage Hoffmeister teaches that vials are thawed, the freezing medium is washed out, and resuspended in a suitable medium (Description, p6; Example 1, p9).
Hoffmeister teaches that following this, cells are transferred to a second (larger) operationally installed meander perfusion bioreactor (Description, p6; Example 1, p9). Hoffmeister teaches that the second bioreactor has a settlement ratio of 3:1 to 20:1 (Description, p6), which overlaps with the claimed range of “a larger settlement area in the ratio of 5 to 1” as in claim 1.
Hoffmeister teaches that media in the bioreactors is perfused with oxygen and is regulated (thus, “in a directed manner”) (Description, p3, 8).
In regards to the medium, Hoffmeister teaches that the medium is supplemented with AB human serum, cytokines, and antibodies (Description, p6 and 9), that oxygen conditions can be hyperoxemic (hyperoxic) (Description, p6), and automatically controlled (Description, p8).
Hoffmeister teaches that the cells grow from the bottom surface (thus, at the bottom of the sedimentation) of the channel of the meander perfusion bioreactor (claim 1).
In regards to whether the cells are largely dormant after sedimentation, and form a cell layer in which they touch and light movements occur, Applicant should note that this appears to be a property or natural consequence of culturing TILs in a perfusion meander bioreactor as in claim 1, not an active method step. Since Hoffmeister teaches culturing TILs in the same bioreactor, they would be expected to also be largely dormant after sedimentation, and form a cell layer in which they touch and light movements occur absent evidence to the contrary.
In regards to the amounts of cells, Hoffmeister teaches that more than 500 million (5 x 108) TILs can be regularly expanded in the bioreactor (Example 1, p9). Hoffmeister also teaches that the bottom of the bioreactor (sedimentation layer) can be between 30 and 500 cm2 (claim 1). Taken together a bioreactor with a 500 cm2 bottom would produce cells at a concentration of 1 x 106 TIL/cm2 which overlaps with the claimed ranges.
While, as above, Hoffmeister teaches that the medium is supplemented with cytokines and antibodies, Hoffmeister is silent as to the specific types of cytokines or antibodies.
In regards to the cytokine being IL-12, a person of ordinary skill in the art would have been motivated to stimulate TILS with the cytokine being IL-12 because Diaz-Montero teaches that IL-12 primed CD8+ T cell populations show superior anti-tumor activity and that culturing naïve CD8+ T cells with IL-12 rescues subsets from in reduced cell death and increased accumulation (Abstract, p564). Furthermore, because Diaz-Montero teaches that T cells can be primed in the presence of the cytokine IL-12 (Fig. 4) and because as above, Hoffmeister teaches that the medium is supplemented with cytokines, it could have been done with predictable results and a reasonable expectation of success.
In regards to the antibody being 4-1BB, a person of ordinary skill in the art would have been motivated to stimulate TILs with the antibody being 4-1BB because Chacon teaches that 4-1BB antibody increases yield of CD8+ T cells, increases their anti-tumor CTL activity, produces T cell populations capable of improved effector function and survival, and suggests that this improves TIL persistence and anti-tumor activity in vivo after adoptive transfer into patients (Abstract, p1). Furthermore, because Chacon teaches that T cells can be contacted with 4-1BB antibody (Results, p4-5; Fig. 1, p5), and because as above, Hoffmeister teaches that the medium is supplemented with antibodies, it could have been done with predictable results and a reasonable expectation of success.
In regards to claim 2, as above, Hoffmeister teaches that the medium is supplemented (Description, p6 and 9), and that TILs expanded in the bioreactor (Example 1, p9 Example 2, p9), and therefore, are “appropriately” supplemented.
Therefore, the combined teachings of Hoffmeister, Diaz-Montero, and Chacon renders the invention unpatentable as claimed.
Claims 3 is rejected under 35 U.S.C. 103 as being unpatentable over Hoffmeister et al. (WO2020078498, published 04/23/2020, on IDS 01/02/2024) in view of Diaz-Montero et al. (Cancer Immunology Immunotherapy) and Chacon et al. (PLOS ONE, 2013), as applied to claims 1 and 2 above, and further in view of MP Biomedicals (Cat. No. 092780248, 2019), Li et al. (Cytotherapy, 2019), Lotze et al. (US20200121719A1, 2020), and Becherucci et al. (Biopreservation and Biobanking, 2020).
In regards to claim 3, as above, Hoffmeister teaches that cryopreserved vials are thawed, the freezing medium is washed out, and resuspended in a suitable medium (Description, p6; Example 1, p9).
While Hoffmeister is silent on whether washing out was performed by centrifugation, a person of ordinary skill in the art would have been motivated to wash out cryopreservation medium by centrifugation because as taught by MP Biomedicals centrifugation is a known technique for washing and recovering cryopreserved cells (column 2). Furthermore, because it is well-established in the art that thawed cells are centrifuged to remove cryopreservation medium, because MP Biomedicals teaches that centrifugation is a suitable technique to remove cryopreservation medium, and because in other steps Hoffmeister teaches that TILs can be centrifuged for separation (Description, p9), it could have been done with predictable results and a reasonable expectation of success.
As above, Hoffmeister teaches that following this, cells are transferred to a second (larger) operationally installed meander perfusion bioreactor (Description, p6; Example 1, p9).
Hoffmeister also teaches that TILs expand over 12 to 20 days and then are washed in a NaCl solution(Description, p6; Example 1, p9).
In regards to centrifugation, a person of ordinary skill in the art would have been motivated to centrifuge cells in order to remove them from contaminating media. Furthermore, because in other steps, Hoffmeister teaches that TILs can be centrifuged to separate them and because it is well-established in the art that cells are centrifuged for separation from media, it could have been done with predictable results and a reasonable expectation of success.
Hoffmeister is silent as to the concentration of NaCl, and does not explicitly teach that the solution comprises 2% albumin or 10% DMSO.
Furthermore, while Hoffmeister teaches that cryopreserved cells are stored over nitrogen (Description, p9), Hoffmeister also does not explicitly teach a step of further resuspending cells in defined portions in 100 mL cryobags after a conventional cooling process and stored over nitrogen (thus, a second cryopreservation step)
However, a person of ordinary skill in the art would have been motivated to subsequently cryopreserve expanded TILs (which would require a “conventional” cooling process) in order to save them for further use. Additionally, because Hoffmeister teaches that TILs may be cryopreserved, it could have been done with predictable results and a reasonable expectation of success.
In regards to the solution (cryopreservation medium), a person of ordinary skill in the art would have been motivated to use a solution comprising DMSO and albumin, because Li teaches that T cells and other immune cells are commonly cryopreserved in media comprising DMSO and albumin and that this is suitable for clinical application (Abstract, p1; Cryopreserved T lymphocytes in clinical trials, p45). Furthermore, because Li teaches that it is well-known in the art that T cells are cryopreserved with DMSO (Abstract, p1; Cryopreserved T lymphocytes in clinical trials, p45; Table 1, p20) it could have been done with predictable results and a reasonable expectation of success.
In regards to the concentrations, Li teaches that T cells are cultured at 10% DMSO which overlaps with the range as in claim 3.
In regards to albumin, Li teaches known formulations with 5% human serum albumin (Table 1, p20), which is close to the claimed 2% (see MPEP 2155.05, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985).
Additionally, a person of ordinary skill in the art could have arrived at a concentration of 2% by routine optimization and the disclosure does not point to a criticality in this percentage (see MPEP 2144.05(II)(A), 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)). In the instant case, because Li teaches that it is known in the art that T cells are cryopreserved in media supplemented with albumin at a range of concentrations (from 5% to 50%)(Table 1, p20), a person of ordinary skill in the art could have arrived at a concentration of 2% by routine optimization with predictable results and a reasonable expectation of success.
In regards to the concentration of NaCl, Li teaches that known formulation of cryopreservation media comprise 0.45% NaCl, which is also close to the claimed 0.9% (Table 20, p1; indeed, PlasmaLyte-A comprises 0.45% NaCl, 5% HSA, and 7.5% DMSO, which is close to the claimed percentages of 0.9%, 2%, and 10% respectively).
Furthermore, a person of ordinary skill in the art could have arrived at a concentration of 0.9% NaCl by routine optimization, the disclosure does not point to a criticality in this concentration, and because Li teaches that it is known that lymphocytes can be cultured in a range of NaCl, from 0.45% NaCl (table 1, p20) to 0.9% (Table 2, p22), a person of ordinary skill in the art could have arrived at the concentration of 0.9% NaCl by routine optimization with predictable results and a reasonable expectation of success.
A person of ordinary skill in the art would have been motivated to store cryopreserved cells over nitrogen because Li teaches that it is known in the art that T cells can be stored in liquid nitrogen for therapeutic use (Table 1, p20).
In regards to a cryobag (a cryopreservation bag), a person of ordinary skill in the art would have been motivated to use a cryobag because Becherucci teaches that blood cells may be stored with a controlled rate of freezing and in nitrogen in cryobags that store volumes between 80 and 150 mL, which overlaps with the range of 100 mL, and stored for at least 6 months (Abstract, p454; Table 1, p455). Furthermore, because Becherucci demonstrates that blood cells may effectively be cryopreserved in bags ((Abstract, p454; Fig. 2, p457) it could have been done with predictable results and a reasonable expectation of success.
Finally, as above, Hoffmeister teaches that frozen vials are thawed (Description, p6; Example 1, p9). A person of ordinary skill in the art would have recognized that this would require retrieving those vials. Furthermore, as above, Hoffmeister teaches that these cells are useful for therapeutic applications and transplantation purposes (Description, p5-6). While Hoffmeister is silent on whether the TILs are specifically dosed to the patient, a person of ordinary skill in the art would have been motivated to dose cells to patients in order to not elicit a pathological immune response and to ensure an adequate amount of therapeutic cells. Furthermore, because Lotze teaches that populations of TILs can be dosed to patients (claim 20), it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Hoffmeister, Diaz-Montero, Chacon, MP Biomedicals, Li, Becherucci, and Lotze renders the invention unpatentable as claimed.
Claims 4 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Hoffmeister et al. (WO2020078498, published 04/23/2020, on IDS 01/02/2024) in view of Diaz-Montero et al. (Cancer Immunology Immunotherapy) and Chacon et al. (PLOS ONE, 2013), as applied to claims 1 and 2 above, and further in view of Lotze et al. (US20200121719A1, 2020).
In regards to claims 4 and 5, since as above, Hoffmeister teaches that these cells are useful for therapeutic applications and transplantation purposes (Description, p5-6), a person of ordinary skill in the art would have recognized that the TIL composition of Hoffmeister is a pharmaceutical composition.
Additionally, as above, since is well-known in the art that as TILs come from a patient’s own tumor cells, a person of ordinary skill in the art would have recognized that pharmaceutical composition is used for the treatment of tumors.
Additionally, as taught by Lotze, it was known in the art before the effective filing date that TILs could be formulated as pharmaceutical compositions for the treatment of cancers including ovarian cancer (claim 139). A person of ordinary skill in the art would have been motivated to utilize the TIL composition of Hoffmeister as a pharmaceutical composition for treating cancers, such as ovarian cancer, to alleviate disease in these patients. Furthermore, because Hoffmeister teaches that the TIL composition can be sued for therapeutic applications and because Lotze teaches that TIL pharmaceutical compositions can be specifically used for treating cancers such as ovarian cancer, it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Hoffmeister, Diaz-Montero, Chacon, and Lotze renders the invention unpatentable as claimed.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPH (PAUL) MIANO whose telephone number is (571)272-0341. The examiner can normally be reached Mon-Fri from 8:30am to 5:30pm.
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/JOSEPH PAUL MIANO/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631