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 .
Claims 1, 2, 4-7, 9, 10, 12, 14, 16, 18, 21, 23, 25, 26, 29-36, 38, 40-43, 48-51 and 54 are pending in this application.
Election/Restrictions
Applicant’s election without traverse of Group I (Claims 1, 2, 4-7, 9, 10, 12, 14, 16, 18, 21, 23, 25, 26, 29-32) and of the species (immunomodulator: OX40L) in the reply filed on 08/14/2026 is acknowledged. Claims 33-36, 38, 40-43, 48-51 and 54 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08/14/2023.
Claims 1, 2, 4-7, 9, 10, 12, 14, 16, 18, 21, 23, 25, 26, 29-32 were examined on their merits.
Specification
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because it is too short to describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Interpretation
Claims 7, 10, 12, 14, 16, 18 and 26 contain optional limitations. The broadest reasonable interpretation of an optional limitation is that it is not required to occur. Therefore, the claims have been construed as not requiring the optional limitations. The Examiner notes that Claim 21 further limits an optional limitation, therefore based on the above interpretation, Claim 21 is also construed as not being required to occur.
Claim 2 recites a contingent limitation, “…and, adjusted if necessary…”. Consistent with the MPEP at 2111.04, II., the broadest reasonable interpretation of a method claim having a contingent limitation requires only those steps which must be performed and does not include steps that are not required to be performed because the conditions precedent are not met. Therefore, the claim has been construed as “a culture medium in which at least two, three, four or all of culture medium parameters is/are monitored, said culture medium parameters comprising pH, dissolved oxygen, glucose concentration, lactate concentration and/or temperature”.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 2, 4-7, 9, 10, 12, 14, 16, 18, 21, 23, 25, 26, 29-32 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. The Examiner notes the use of the term
“conditioned medium”, customarily the term describes a nutrient rich media that previously supported cell growth and contains substances secreted by those cells. It is unclear how the term is being used in the claim such that the metes and bounds of the claim can be determined in light of the Specification. For example, the Specification as published at Pg. 10, Paragraph [0186] as well as instant Claims 1-2 indicate that a “conditioned medium” is any medium in which certain parameters of the culture medium are monitored throughout the entire process and are adjusted to predefined values if necessary. For purposes of examination, the term has been construed thusly. Claims 2, 4-7, 9, 10, 12, 14, 16, 18, 21, 23, 25, 26, 29-32 are rejected as being dependent upon Claim 1 and for failing to rectify the indefiniteness thereof.
Claim 2 recites, “wherein the conditioned culture medium is a culture medium in which at least one, two, three, four or all of culture medium parameters is/are monitored and adjusted if necessary, said culture medium parameters comprising: pH, dissolved oxygen (DO) concentration, glucose concentration, lactate concentration and/or temperature”. It is unclear if the limitation is intended to further limit the method steps of Claim 1 or the conditioned culture medium of Claim 1.
For example, the claim does not recite any active method steps or limitations which further modify either the recited method steps or the conditioned medium as “monitoring” is passive and the adjustment is a contingent limitation. For purposes of examination the claim has been interpreted as actively measuring the culture medium parameters.
Claims 7 and 9 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 Claims 7 and 9, the phrase "in particular" renders the claims indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 103
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.
Claims 1, 4, 5, 7, 9, 12, 14, 16, 18, 23, 25, 26, 29, 30, 31 and 32 are rejected under 35 U.S.C. § 103 as being unpatentable over Bobisse et al. (WO 2019/086711 A1), cited in the IDS.
Bobisse et al. teaches expanding/culturing lymphocytes in a sample from a subject (Pg. 85, Claim 1),
wherein the sample can be a tissue sample (tumor fragment) or a bodily fluid sample (Pg. 93, Claim 88), wherein the bodily fluid is blood (Pg. 94, Claim 90);
during the expanding/culturing adding one or more peptides comprising a different antigen (Pg. 85, Claim 1);
wherein the lymphocytes are tumor infiltrating lymphocytes (TILs) (Pg. 93, Claim 85);
wherein the peptides are presented on the surface of an antigen presenting cell (APC) (thus coculturing the APC and lymphocytes during expansion/culture, see above) (Pg. 86, Claim 16);
wherein the APC is a B-cell (Pg. 94, Claim 99);
wherein the B-cell is activated (Pg. 94, Claim 94);
wherein the APC are genetically engineered to express an immunomodulator (Pg. 90, Claim 49), wherein the immunomodulator is OX40L (Pg. 89, Claim 47);
wherein the antigen is a tumor antigen from a solid tumor, wherein the tumor antigen is a tumor-specific neo-antigen, and wherein antigen-specific lymphocytes are isolated from the sample before culturing (e.g. the presence of the neo-antigen in the tumor sample is confirmed prior to culturing) (Pg. 95, Claims 103, 104 and 111);
wherein the medium is supplemented with IL-2 (Pg. 91, Claims 60-63);
wherein the culture process provides a final T-cell population of 109-1011 (Pgs. 1-2, Paragraph [0004]);
wherein the expanded lymphocytes have an expansion rate (Pg. 12, Paragraph [0048] and Fig. 13);
wherein the culturing is performed under appropriate conditions necessary to support cell growth, for example and appropriate temperature (37 °C) and atmosphere (air and CO2) and in the presence of pH buffers (Pg. 55, Paragraph [00212]);
and wherein the peptides can be identified by sequencing enzymatic digests using mass spectrometry (Pg. 44, Paragraph [00170]), and reading on Claims 1, 7, 9, 10, 12, 14, 18, 23, 29, 30 and 31.
The teachings of Bobisse et al. were discussed above.
Bobisse et al. did not teach a method wherein in a single, controlled (note definition in published Specification at Pg. 34, Paragraph [0246]) culture vessel, the lymphocytes are cultured in a conditioned medium in which pH, temperature and dissolved oxygen are measured, as required by Claim 1,
wherein the volume of medium is adjusted according to the expansion rate of the lymphocytes, as required by Claim 4;
wherein the medium volume increases by at least a factor of 2, 3, 4, 5 or 6 during lymphocyte expansion, as required by Claim 5;
wherein the B-cells are activated prior to addition to the lymphocytes or activated during culturing, as required by Claims 16 and 26;
wherein confirming the presence of the one or more antigens in the tumor sample comprises sequencing genomic DNA obtained from the tumor sample, as required by Claim 25;
or wherein the sample or lymphocytes are maintained at temperatures greater than 0 °C subsequent to isolation from said subject and prior to culture, as required by Claim 32.
With regard to Claim 1, it would have been obvious to those of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Bobisse et al. comprising performing culturing under appropriate conditions necessary to support cell growth, for example and appropriate temperature (37 °C) and atmosphere (air and CO2) and in the presence of pH buffers, to perform the culturing in a discrete apparatus, such as an incubator or bioreactor, in which it would be possible to measure the culture medium for those parameters in order to maintain the conditions necessary for lymphocyte growth. Those of ordinary skill in the art would have been motivated to make this modification in order to grow and/or maintain alive the desired cells. There would have been a reasonable expectation of success in making this modification because the reference already teaches the parameters and the ordinary artisan would have been aware of the general culture parameters necessary for cell culturing.
With regard to Claims 4 and 5, it would have been obvious to those of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Bobisse et al. wherein the cultured lymphocytes have an expansion rate to adjust the medium volume based on the expansion rate because the expansion rate tells the practitioner how fast the lymphocytes are growing and consequently how much more medium is needed to provide the nutrients and space to maintain and contain the expanding lymphocyte population. While the reference listed above does not specifically teach the limitations of adjusting media volume according to the expansion rate of the lymphocytes or wherein the medium volume increases by at least a factor of 2, 3, 4, 5 or 6 during lymphocyte expansion, one of ordinary skill in the art would recognize that the amount of media added in a culture based on cell expansion rate and the factor by which the volume increases are result-effective optimizable variables. Bobisse et al. demonstrates that lymphocytes expand by a multi-fold rate (see Fig. 13). Those of ordinary skill in the art would expect that as a cell population expands so to would the need for additional medium to accommodate the expanding population. This is motivation for someone of ordinary skill in the art to practice or test the parameter values widely to find those that are functional or optimal for maintaining cell health and growth which then would be inclusive or cover that values as instantly claimed.
Absent any teaching of criticality by the Applicant concerning the adjustment of media volume according to the expansion rate of the lymphocytes or wherein the medium volume increases by at least a factor of 2, 3, 4, 5 or 6 during lymphocyte expansion, it would be prima facie obvious that one of ordinary skill in the art would recognize these limitations are an optimizable variable which can be met as a matter of routine optimization (see MPEP § 2144.05 (II)(B).
With regard to Claims 16 and 26, it would have been obvious to those of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Bobisse et al. comprising coculturing the APC and lymphocytes during expansion/culture, wherein the APC is a B-cell and wherein the B-cell is activated to activate the B-cells either prior to or during culture with the lymphocytes because this is no more than the selection from a finite number of identified, predictable solutions with a reasonable expectation of success. See KSR, MPEP 2143, I., E. That is, B-cells to act as APC B-cells requires activation and activation can only occur: prior to, during or after contact with lymphocytes in culture and the ordinary artisan could have selected the optimal or desired activation time with a reasonable expectation of success.
With regard to Claim 25, it would have been obvious to those of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Bobisse et al. comprising wherein tumor neoantigen-specific lymphocytes are isolated from a tumor before culturing (e.g. the presence of the neo-antigen in the tumor sample is confirmed prior to culturing) to confirm the presence of the antigen/peptides by sequencing enzymatic digests (of the tumor sample) using mass spectrometry because this would allow specific identification of the desired neoantigens/peptides in the tumor sample prior to further methodology. Those of ordinary skill in the art would have been motivated to make this modification in order to determine if the desired antigen/peptide is present in the sample and eliminate the need for unnecessary method steps if it is not. There would have been a reasonable expectation of success in making this modification because Bobisse et al. teaches determining the presence of neo-antigen/peptide in the tumor sample prior to culturing as well as sequence analysis of digested samples to identify peptides.
With regard to Claim 32, it would have been obvious to those of ordinary skill in the art before the effective filing date of the claimed invention that the tissue or blood sample or lymphocytes are maintained at temperatures greater than 0 °C subsequent to isolation from said subject and prior to culture because this is no more than the selection from a finite number of identified, predictable solutions with a reasonable expectation of success. See KSR, MPEP 2143, I., E.
That is, samples (tissue, blood, cells) can only be maintained at temperatures either above or below 0 °C subsequent to isolation from said subject and prior to culture and the ordinary artisan could have selected the optimal or desired temperature with a reasonable expectation of success.
Claims 1, 4, 5, 6, 7, 9, 12, 14, 16, 18, 23, 25, 26, 29, 30, 31 and 32 are rejected under 35 U.S.C. § 102(a)(1) as being anticipated by Bobisse et al. (WO 2019/086711 A1), as applied to Claims 1, 4, 5, 7, 9, 12, 14, 16, 18, 23, 25, 26, 29, 30, 31 and 32 above, and further in view of Garcia-Aponte et al. (04/13/2021), both cited in the IDS.
The teachings of Bobisse et al. were discussed above.
Bobisse et al. did not teach dynamic culturing of the lymphocytes in the culture medium, as required by Claim 5.
Garcia-Aponte et al. teaches that cell culturing may be performed under either static or dynamic conditions in a bioreactor (Pg. 5, Fig. 2).
It would have been obvious to those of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Bobisse et al. comprising expanding/culturing lymphocytes, to perform the expansion/culturing under dynamic conditions because this is no more than the selection from a finite number of identified, predictable solutions with a reasonable expectation of success.
See KSR, MPEP 2143, I., E. That is, the art recognizes that cell culturing is performed only under static or dynamic conditions and the ordinary artisan could have selected the optimal or desired culturing method with a reasonable expectation of success.
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, 4-7, 9, 10, 12, 14, 16, 18, 21, 23, 25, 26, 29-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7, 11-14, 16, 18, 21, 23, 25, 38, 39, 40 and 41 of copending Application No. 19/126,511(reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims 1, 2 and 4 are drawn to:
A method for expansion of a population of lymphocytes specific for one or more antigens in a controlled single culture vessel, the method comprising:
culturing a tissue or blood sample from a subject in the presence of said one or more antigens, wherein said tissue or blood sample is known or suspected to contain lymphocytes; or
culturing lymphocytes in the presence of said one or more antigens, wherein said lymphocytes are isolated from a tissue or blood sample from a subject;
wherein the lymphocytes are cultured in a conditioned culture medium,
wherein the conditioned culture medium is a culture medium in which at least one, two, three, four or all of culture medium parameters is/are monitored and adjusted if necessary, said culture medium parameters comprising: pH, dissolved oxygen (DO) concentration, glucose concentration, lactate concentration and/or temperature,
and the expansion of the lymphocytes exhibits an expansion rate, and wherein the method further comprises-adjusting volume of the conditioned culture medium according to the expansion rate of the lymphocytes.
This is made obvious by Claims 1 and 8 of the co-pending ‘511 Application which is drawn to:
A method for expansion of a population of lymphocytes in a controlled single culture vessel, the method comprising a step of:
culturing a tissue or blood sample from a subject, which sample is known or
suspected to contain lymphocytes; or
culturing lymphocytes, which lymphocytes are isolated from a tissue or blood
sample from a subject;
wherein the lymphocytes are expanded in a culture medium in which at least
one of the following parameters is monitored and adjusted to a predefined value or
range: pH, dissolved oxygen (DO) concentration, glucose concentration, lactate concentration and/or temperature; and
wherein the method comprises a step of adjusting the culture volume to the
expansion rate of the lymphocytes,
and wherein the lymphocytes are expanded in the presence of one or more antigen.
Instant Claims 2&4, 5-25 and 29-32 correlate with Claims 1, 3-5, 7, 11-14, 16, 18, 21, 23, 25 and 38-41 of the co-pending ‘511 application.
The co-pending ‘511 application does not teach a method comprising activating the lymphocytes during culturing, as required by instant Claim 26.
With regard to Claim 26, it would have been obvious to those of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of the ‘511 application comprising activating the B-cells either prior to culture to activate the B-cells during culture with the lymphocytes because this is no more than the selection from a finite number of identified, predictable solutions with a reasonable expectation of success. See KSR, MPEP 2143, I., E. That is, B-cells to act as APC B-cells requires activation and activation can only occur: prior to, during or after contact with lymphocytes in culture and the ordinary artisan could have selected the optimal or desired activation time with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to PAUL C MARTIN whose telephone number is (571)272-3348. The Examiner can normally be reached Monday-Friday 12pm-8pm EST.
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, Sharmila G Landau can be reached at (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PAUL C MARTIN/ Examiner, Art Unit 1653 08/31/2026
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