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 .
Election/Restrictions
Applicant’s election without traverse of Group I (Claims 1-2, 5-6, 8-11, 13, 15, 17-18, 20-22, 24, and 31-32; drawn to a method for culturing genetically modified cells) in the reply filed on September 22, 2025, is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 33 and 35 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (Group II), there being no allowable generic or linking claim.
Applicant further elected the following species:
a. microbead diameter from about 1 μm to about 10 μm
b. microbead cell ratio from about 0.5 to about 5
c. Activating agent of anti-CD3 antibodies or fragments thereof
In light of the Applicant’s elected species, claim 5 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
The species election requirement for the activating agent has been reconsidered in view of the prior art. Anti-CD28 antibodies are rejoined.
DETAILED ACTION
The amended claims filed on September 22, 2025, have been acknowledged. Claims 3-4, 7, 12, 14, 16, 1923, 25-30, and 34 were cancelled. In light of the Applicant’s elected invention and species, claims 5, 33, and 35 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1-2, 6, 8-11, 13, 15, 17-18, 20-22, 24, and 31-32 are pending and examined on the merits.
Priority
Acknowledgment is made of Applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d).The applicant claims foreign priority from CN2020105366876 filed on June 12, 2020. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55, received December 9, 2022. While a certified copy of the foreign patent application CN2020105366876 is provided with the instant application, a certified English translation of said foreign patent application has not been provided.
Information Disclosure Statement
The information disclosure statements (IDS) filed on December 9, 2022, March 22, 2023, August 6, 2024, June 4, 2025, have been considered.
Claim Interpretation
Claim 1 is interpreted to only requires step (a) as step (b) is optional and step (c) requires the pretreated immune cells of step (b). As such, steps (b)-(f) are considered optional steps.
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.
Claim 1 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01.
As an initial matter, this rejection is based on the interpretation that steps (b)-(f) are optional and not required for the method of claim 1.
Claim 1 claims a method for culturing genetically modified immune cells but the only active step is providing a sample containing immune cells.
The required omitted steps are: genetically modifying immune cells and culturing the genetically modified immune cells.
As can be seen in claim 1 and Examples 1-2, providing a sample containing immune cells is not sufficient for culturing genetically modified immune cells. Additional steps of genetically modifying the cells and, then, culturing them are required as the initial sample does not have genetically modified immune cells.
Claims 2, 6, 8-11, 13, 15, 17-18, 20-22, 24, and 31-32 are not included in this rejection because step all dependent claims are treated as though optional step (b) was performed as part of the claim, for compact prosecution. Therefore, steps (c)-(f) would also be performed as they would also no longer be optional steps.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claim 1 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural process without significantly more.
As an initial matter, this rejection is based on the interpretation that steps (b)-(f) are optional and not required for the method of claim 1.
Claim 1 claims a method for culturing genetically modified immune cells but the only active step is providing a sample containing immune cells. Claim 1 has a broadest reasonable interpretation that encompasses a process of collecting blood from a subject. Regarding the genetic modified immune cells, this has a broadest reasonable interpretation that encompasses naturally occurring spontaneous mutations, Therefore, claim 1 has a broadest reasonable interpretation that encompasses collecting blood (which contains immune cells) that contain spontaneous mutations. As such, claim 1 reads on a natural process. This judicial exception is not integrated into a practical application because the natural process is not linked to a particular technology. The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because the only active step is providing a sample containing immune cells.
Applicant is directed to the 2019 Revised Patent Subject Matter Eligibility Guidance published in the Federal Register (84 FR 50) on 1/07/2019, which is found at: https://www.govinfo.gov/content/pkg/FR-2019-01-07/pdf/2018-28282.pdf; and the October 2019 Update: Subject Matter Eligibility, which is found at https://www.uspto.gov/sites/default/files/documents/peg_oct_2019_update.pdf.
Briefly summarized here, the new guidance cites a two part test: is the claimed invention directed to a statutory class of invention (Step 1), if so then is the claimed invention as a whole directed to a law of nature, natural phenomena, or an abstract idea (i.e. set forth or described in the claim) (Step 2A, prong one), if so then is the claimed invention recite additional elements that integrate the judicial exception into a practical application (Step 2A, prong two), if not then does the claim as a whole amount to significantly more than the judicial exception (Step 2B).
In regard to Step 1, Claim 1 is drawn to a process.
In regard to Step 2A prong one, Claim 1 is drawn to a natural process.
Specifically, claim 1 is directed to a method for culturing genetically modified immune cells but the only active step is providing a sample containing immune cells. Claim 1 has a broadest reasonable interpretation that encompasses collecting blood (which contains immune cells) that contain spontaneous mutations. As such, claim 1 reads on a natural process. Accordingly, instant claims are directed to a judicial exception.
In regard to Step 2A prong two, the judicial exception is not integrated into a practical application. In particular, Claim 1 recites no additional elements to integrate the claimed natural process into a practical application.
In regard to Step 2B, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. As stated supra, Claim 1 recites no additional elements to the natural process of providing a sample containing immune cells.
Therefore, Claim 1 is directed to a natural process that is not integrated into a practical application and does not include elements that amount to significantly more than the natural process itself. Therefore, claim 1 does not qualify as patent eligible subject matter under 35 U.S.C. § 101.
Claims 2, 6, 8-11, 13, 15, 17-18, 20-22, 24, and 31-32 are not included in this rejection because step all dependent claims are treated as though optional step (b) was performed as part of the claim, for compact prosecution. Therefore, steps (c)-(f) would also be performed as they would also no longer be optional steps.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 1 is rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by United States Patent Application No. 2019/0367876 (Frost).
As an initial matter, this rejection is based on the interpretation that steps (b)-(f) are optional and not required for the method of claim 1.
Claim 1 claims a method for culturing genetically modified immune cells but the only active step is providing a sample containing immune cells.
Frost teaches a method of collecting blood from a subject including peripheral blood mononuclear cells (i.e. immune cells) (paragraphs 0053 and 0058). As stated supra, these immune cells can have naturally occurring spontaneous mutations that would read on genetically modified immune cells.
Claims 1, 8-11,13, 15, 17-18, 20-22, 24, and 32 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by United States Patent Application No. 2019/0367876 (Frost).
As an initial matter, this rejection is based on step (b) being practiced and, thus, steps (c)-(f) being practiced, as well.
Regarding claim 1, Frost teaches a method of culturing genetically modified immune cells comprising:
Collecting blood containing peripheral blood mononuclear cells (PBMCs) from a subject (paragraphs 0053 and 0058, Figure 1, and claims 1 and 49);
Washing the blood sample before enriched PBMCs are isolated as part of the enrichment process (paragraphs 0059-0061);
Sorting the blood to isolate PBMCs to obtain an enriched PBMC population. Furthermore, the enriched PBMC population can be undergo magnetic sorting for purifying T cells and/or NK cells through positive selection or monocytes and/or macrophages can be removed using magnetic bead activated cell sorting through negative selection (paragraphs 0059-0060 and claim 1);
Activating the enriched T cells and/or NK cells by adding anti-CD3 and/or anti-CD28 immobilized on a bead to the media comprising the enriched T cells and/or NK cells (paragraphs 0064-0070 and claims 1 and 18);
Genetically modifying the T cells and/or NK cells by contacting the cells ex vivo with replication incompetent recombinant retroviral particles (paragraphs 0071-0076 and claim 1); and
Expanding the genetically modified T cells and/or NK cells (paragraphs 0077-0088 and claim 1)
Regarding claims 8-9, Frost teaches that the activating agent can be anti-CD3 and/or anti-CD28 immobilized on beads.
Regarding claim 10, Frost teaches that the T cells and/or NK cells can be incubated with the one or more activating agents for 24 hours (paragraph 0070).
Regarding claim 11, Frost teaches that the activating step can last 12 hours, the transduction step can last 12 hours, and the expansion step can last 4 days (paragraphs 0070, 0073, and 0088).
Regarding claim 13, Applicant does not define about. A reasonable interpretation of about is ± 20%. As can be seen in figure 1, the steps of blood collection to cell activation can all occur within the same 24 hour period before transducing the activated cells the next day. Furthermore, Frost teaches that the transduction step can last 12 hours and the expansion step can last 4 days (paragraphs 0073 and 0088). As such, this would equate to steps (a)-(d) lasting for 24 hours, step (e) lasting 12 hours, and step (f) lasting 4 days which is 5.5 days and would be within the about 5 days (up to 6 days) of claim 13.
Regarding claim 15, Frost teaches that a single reactor, fed-batch process can be used for the enrichment, activation, transduction, and expansion of T cells and/or NK cells in a closed system (paragraphs 0048-0057).
Regarding claim 17, as stated supra, Frost teaches that blood contains T cells (paragraphs 0058-0060).
Regarding claim 18, Frost teaches that as part of their activation method, PBMCs can be seeded at a density of 4 x106 cells/mL (paragraph 0065 and claim 6).
Regarding claim 20, Frost, as stated supra, teaches that they transduced the activated T cells and/or NK cells (claim 1).
Regarding claim 21, Frost teaches that the T cells and/or NK cells can be genetically modified with retroviral particle comprising a retroviral genome a chimeric antigen receptor (CAR) (claim 14).
Regarding claim 22, Frost teaches that the retroviral particle can be a lentivirus (paragraph 0071).
Regarding claim 24, Frost teaches that the washing step can comprise using a washing solution comprising human serum albumin with a final concentration of 0.25-10% (paragraph 0061).
Regarding claim 32, Frost teaches that they collected peripheral blood (paragraph 0058).
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.
Claims 1-2 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over United States Patent Application No. 2019/0367876 (Frost) as applied to claim 1 above, and further in view of Kalamasz et al. (J Immunother 27: 405-418. 2004).
Regarding claim 2, the teachings of Frost are as discussed above.
Frost is silent as to which beads with anti-CD3 and/or anti-CD28 are used as part of their method.
However, Kalamasz teaches that Xcyte Dynabeads can be used to attach anti-CD3 and anti-CD28 for activation of T cells. Kalamasz teaches that these beads have a diameter of 4.5 μm. Kalamasz teaches that T cells produced from activation with Xcyte Dynabeads have been shown to have a strong safety record (abstract and page 406, column 1, paragraph 1-page 408, column 1, paragraph 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the Xcyte Dynabeads attached with anti-CD3 and anti-CD28 for activation of T cells, as identified by Kalamasz, in the activation method of Frost to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to use the Xcyte Dynabeads attached with anti-CD3 and anti-CD28 for activation of T cells with a reasonable expectation of success because Kalamasz teaches that these were a known set a beads that can successfully activate T cells and that activating T cells with these beads has already been shown to be safe for later use with humans. Therefore, it would have been obvious that the Dynabeads of Kalamaz could be used for activating the T cells of Frost as they had previously been used for this function and are considered safe. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 6, the teachings of Frost are as discussed above.
Frost is silent as to the ratio of beads-to-cell as part of their activation method.
However, Kalamasz teaches that Xcyte Dynabeads can be used to attach anti-CD3 and anti-CD28 for activation of T cells. Kalamasz teaches that T cell expansion was maximal when the number of beads and T cells were equal (i.e. 1:1). Furthermore, Kalamasz teaches that T cells produced from activation with Xcyte Dynabeads have been shown to have a strong safety record (abstract, page 406, column 1, paragraph 1-page 408, column 1, paragraph 1, page 411, column 2, paragraph 2, and Figure 9).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the Xcyte Dynabeads attached with anti-CD3 and anti-CD28 at a ratio of 1:1 for activation of T cells, as identified by Kalamasz, in the activation method of Frost to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to use the Xcyte Dynabeads attached with anti-CD3 and anti-CD28 for activation of T cells at a ratio of 1:1 with a reasonable expectation of success because Kalamasz teaches that these were a known set a beads that can successfully activate T cells and that activating T cells with a bead-to-cell ratio of 1:1 led to the most T cell expansion. As the goal of the method of Frost is to genetically modify T cells, it would have been obvious that increasing the expansion of the T cells during activation would increase the number of T cells that can be genetically modified, improving the number of genetically modified cells that can achieved from the method of Frost. Therefore, it would have been obvious to use the Dynabeads of Kalamasz as they had previously been used for this function and are considered safe, and it would have been obvious to use a 1:1 bead-to-cell ratio to achieve a higher output of genetically modified T cells. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claims 1 and 31 are rejected under 35 U.S.C. 103 as being unpatentable over United States Patent Application No. 2019/0367876 (Frost) as applied to claim 1 above, and further in view of United States Patent Application No. 2019/0247433 (Kalra).
The teachings of Frost are as discussed above.
Although Frost teaches that the enriched PBMC population can undergo magnetic sorting for purifying T cells (which Frost acknowledges are CD4 and/or CD8+ and directly identifies that they want CD4 and CD8 positive T cells in as part of their population of genetically engineered T cells (paragraphs 0020 and 0162)) through positive selection (paragraphs 0059-0060), Frost is silent as to using anti-CD4 or anti-CD8 antibodies.
However, Kalra teaches that T cells can be selected for using MACS-CD4 and CD8-Microbeads (i.e. CD4 antibody and CD8 antibody bound to a microbead) to enrich for CD4+ and CD8+ T cells (paragraph 0289)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used MACS-CD4 and CD8-Microbeads for magnetic sorting of CD4+ and/or CD8+ T cells, as identified by Kalra, in the sorting method of Frost to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to use the MACS-CD4 and CD8-Microbeads with a reasonable expectation of success because Kalra teaches that these were known to be used for magnetic sorting of CD4+ and CD8+ T cells. As Frost already identifies that T cells can be magnetically sorted and Kalra teaches that the MACS-CD4 and CD8-Microbeads can be used for magnetic sorting, one of ordinary skill in the art would reasonably envision using the MACS-CD4 and CD8-Microbeads for magnetic sorting and enrichment of T cells. Because the prior art teaches all of the elements of the claimed invention, there is 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, 6, 8-11, 13, 15, 17-18, 20-22, 24, and 32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 and 20 of copending Application No. 18/251,469. Although the claims at issue are not identical, they are not patentably distinct from each other.
As an initial matter, this rejection is based on the interpretation that steps (b)-(f) are optional and not required for the method of claim 1.
Claim 1 claims a method for culturing genetically modified immune cells but the only active step is providing a sample containing immune cells.
‘469 claims a method of preparing genetically modifying immune cells comprising:
(a) providing a sample containing immune cells;
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 6, 8-11, 13, 15, 17-18, 20-22, 24, and 32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 and 20 of copending Application No. 18/251,469 in view of United States Patent Application No. 2019/0367876 (Frost).
As an initial matter, this rejection is based on step (b) being practiced and, thus, steps (c)-(f) being practiced, as well.
Regarding claim 1, ‘469 claims a method of preparing genetically modifying immune cells comprising:
(a) providing a sample containing immune cells;
(b) sorting the sample to obtain a first immune cell population enriched in immune cells;
(c) activating the first immune cell population to obtain a second immune cell population (wherein the first immune cell population is activated with microbeads coated with activating agents.);
(d) culturing the second immune cell population to obtain a third immune cell population;
(e) genetically modifying the third immune cell population to obtain a fourth immune cell population; and
(f) culturing the fourth immune cell population to obtain genetically modified immune cells (as step f is culturing the genetically modified cells from step (e), this would also result in expansion of the genetically modified cells) (claims 1 and 2).
‘469 does not teach washing the sample containing the immune cells.
However, Frost teaches a method of culturing genetically modified immune cells comprising:
Collecting blood containing peripheral blood mononuclear cells (PBMCs) from a subject (paragraphs 0053 and 0058, Figure 1, and claims 1 and 49);
Washing the blood sample before enriched PBMCs are isolated as part of the enrichment process (paragraphs 0059-0061);
Sorting the blood to isolate PBMCs to obtain an enriched PBMC population. Furthermore, the enriched PBMC population can be undergo magnetic sorting for purifying T cells and/or NK cells through positive selection or monocytes and/or macrophages can be removed using magnetic bead activated cell sorting through negative selection (paragraphs 0059-0060 and claim 1);
Activating the enriched T cells and/or NK cells by adding anti-CD3 and/or anti-CD28 immobilized on a bead to the media comprising the enriched T cells and/or NK cells (paragraphs 0064-0070 and claims 1 and 18);
Genetically modifying the T cells and/or NK cells by contacting the cells ex vivo with replication incompetent recombinant retroviral particles (paragraphs 0071-0076 and claim 1); and
Expanding the genetically modified T cells and/or NK cells (paragraphs 0077-0088 and claim 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of preparing genetically modified immune cells of ‘469 by including a washing step of the sample containing immune cells, as identified by Frost, to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Frost successfully reduces to practice that a wash step for the blood sample can occur as part of a method of generating genetically modified immune cells. Thus, one of ordinary skill in the art would readily envision that a washing step could be added to the method of ‘469. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 6, ‘469 claims that the activating is performed with a microbead- to-cell ratio ranging from about 0.5:1 to about 5:1 (claims 2-3).
Regarding claims 8-9, ‘469 claims that the activating agent can be anti-CD3 and/or anti-CD28 immobilized on beads (claims 2 and 4-5).
Regarding claim 10, ‘469 is silent as to the length of time of the activation step.
However, Frost teaches that the T cells and/or NK cells can be incubated with the one or more activating agents for 24 hours (paragraph 0070).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used a 12 hour activation step, as identified by Frost, in the sorting method of ‘469 to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to use a 12 hour activation step with a reasonable expectation of success because Frost identifies a similar method of generating genetically modified immune cells to ‘469 and teaches that a 24 hour incubation time for the activation step is reasonable. As such, one of ordinary skill in the art would readily envision that a 24 hour activation step could used in the method of ‘469. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 11, ‘469 claims wherein step (b) to step (f) are performed in about 4 days to about 5 days (claim 11).
Regarding claim 13, ‘469 claims wherein step (b) to step (f) are performed in about 4 days to about 5 days (claim 11). ‘469 does not claim the timeframe associated with performing steps (a)-(f). However, Frost teaches that steps (a)-(d) can all occur within the same 24 hour period. Therefore, step (a) is considered to take less than 24 total hours and if step (b) to step (f) are performed in about 4 days, this would remain within the about 5 days of claim 13.
Regarding claim 15, ‘469 does not claim wherein steps (c)-(f) are performed in a closed and sterile system.
Frost teaches that a single reactor, fed-batch process can be used for the enrichment, activation, transduction, and expansion of T cells and/or NK cells in a closed system (paragraphs 0048-0057). As this would be more sterile than trying to perform this in an open system with multiple manipulation steps, it would have been obvious to perform these steps in a closed and sterile system.
Regarding claim 17, ’469 claims wherein the immune cells are T cells or T cell subsets (claim 15).
Regarding claim 18, ’469 claims wherein in step (c) the activating is performed with a density of the first immune cell population ranging from about 0.5x106 cells/ml to about 10x106 cells/ml (claim 6).
Regarding claims 20 and 22, ’469 claims wherein in step (e) the genetically modifying comprises transducing the third immune cell population with lentiviral vectors, gamma-retroviral vectors, alpha-retroviral vectors, or adenoviral vectors (claim 1).
Regarding claim 21, ’469 claims wherein in step (e) the genetically modifying comprises introducing into the third immune cell population a polynucleotide encoding a chimeric antigen receptor (CAR) or a T cell receptor (TCR) (claim 17).
Regarding claim 22, Frost teaches that the retroviral particle can be a lentivirus (paragraph 0071).
Regarding claim 24, Frost teaches that the washing step can comprise using a washing solution comprising human serum albumin with a final concentration of 0.25-10% (paragraph 0061).
Regarding claim 32, ’469 claims wherein the sample is peripheral blood, cells, fresh apheresis, cryopreserved apheresis, monocyte collections, peripheral blood mononuclear cells (PBMCs), or combinations thereof
This is a provisional nonstatutory double patenting rejection.
Claims 1-2 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 and 20 of copending Application No. 18/251,469 in view of United States Patent Application No. 2019/0367876 (Frost) as applied to claim 1 above and further in view of Kalamasz et al. (J Immunother 27: 405-418. 2004).
Regarding claim 2, the teachings of ‘469 and Frost are as discussed above.
‘469 and Frost are silent as to which beads with anti-CD3 and/or anti-CD28 are used as part of their method.
However, Kalamasz teaches that Xcyte Dynabeads can be used to attach anti-CD3 and anti-CD28 for activation of T cells. Kalamasz teaches that these beads have a diameter of 4.5 μm. Kalamasz teaches that T cells produced from activation with Xcyte Dynabeads have been shown to have a strong safety record (abstract and page 406, column 1, paragraph 1-page 408, column 1, paragraph 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the Xcyte Dynabeads attached with anti-CD3 and anti-CD28 for activation of T cells, as identified by Kalamasz, in the activation method of ‘469 and Frost to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to use the Xcyte Dynabeads attached with anti-CD3 and anti-CD28 for activation of T cells with a reasonable expectation of success because Kalamasz teaches that these were a known set a beads that can successfully activate T cells and that activating T cells with these beads has already been shown to be safe for later use with humans. Therefore, it would have been obvious that the Dynabeads of Kalamaz could be used for activating the T cells of ‘469 and Frost as they had previously been used for this function and are considered safe. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claims 1 and 31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 and 20 of copending Application No. 18/251,469 in view of United States Patent Application No. 2019/0367876 (Frost) as applied to claim 1 above and further in view of United States Patent Application No. 2019/0247433 (Kalra).
The teachings of ‘469 and Frost are as discussed above. ‘469 claims wherein in step (b) the sorting is performed by mixing the sample with sorting magnetic beads and wherein the sorting comprises positive sorting (claims 7-8).
Although ‘469 and Frost teaches that the enriched PBMC population can undergo magnetic sorting for purifying T cells (which Frost acknowledges are CD4 and/or CD8+ and directly identifies that they want CD4 and CD8 positive T cells in as part of their population of genetically engineered T cells (paragraphs 0020 and 0162)) through positive selection (paragraphs 0059-0060), ‘469 and Frost are silent as to using anti-CD4 or anti-CD8 antibodies.
However, Kalra teaches that T cells can be selected for using MACS-CD4 and CD8-Microbeads (i.e. CD4 antibody and CD8 antibody bound to a microbead) to enrich for CD4+ and CD8+ T cells (paragraph 0289)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used MACS-CD4 and CD8-Microbeads for magnetic sorting of CD4+ and/or CD8+ T cells, as identified by Kalra, in the sorting method of ‘469 and Frost to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to use the MACS-CD4 and CD8-Microbeads with a reasonable expectation of success because Kalra teaches that these were known to be used for magnetic sorting of CD4+ and CD8+ T cells. As ‘469 already claims that positive selection using magnetic beads can be used and Frost already identifies that T cells can be magnetically sorted and Kalra teaches that the MACS-CD4 and CD8-Microbeads can be used for magnetic sorting, one of ordinary skill in the art would reasonably envision using the MACS-CD4 and CD8-Microbeads for magnetic sorting and enrichment of T cells. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Conclusion
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/KEENAN A BATES/Examiner, Art Unit 1631
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