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 .
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 teachd 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, 8, 16, 17, 19, 21, 23, 24, 35, 43, 50, 55, 56, 68, and 71-73 are rejected under 35 U.S.C. 103 as being unpatentable over Kaiser et al. (WO 2015/162211 A1) in view of Hegazy et al. (Circulating and Tissue-Resident CD4+ T Cells With Reactivity to Intestinal Microbiota Are Abundant in Healthy Individuals and Function is Altered During Inflammation, 2017)
Regarding Claims 1-4: Kaiser teaches an aspect of the invention which comprises the following steps (pg 3-4, lines 29-7):
Providing a cell population of T cells/subsets/progenitors
Preparing the cell population via centrifugation
Magnetic separation of the cell population
Activation of the enriched cell population using modulatory agents
Genetic modification of the T cells/subsets/progenitors
Expansion of the cell population in a cultivation chamber
Washing the cultured cell population and characterization of said cell population
Kaiser also teaches an embodiment of the invention which uses antigen-binding molecules specific for CCR7 for use in magnetic separation of the T cell population (Pg 4, lines 9-13) and details that the chimeric antigen receptor (CAR) of the invention comprises “comprise an antigen binding domain also known as antigen targeting region, an extracellular spacer domain or hinge region, a transmembrane domain and at least one intracellular signaling domain or at least one co-stimulatory domain and at least one intracellular signaling domain.” (Pg 20, lines 27-30) Lastly, Kaiser teaches an embodiment of the invention which uses viral vectors to perform the genetic modification of the T cells. (Pg 14, lines 6-12) This reads on the claimed method of selecting CCR7+ primary T cells, incubating the T cells under stimulatory conditions with a heterologous polynucleotide encoding a recombinant protein which add one or more components of a T-cell receptor (TCR) complex and/or one or more intracellular signaling domains of one or more costimulatory molecules, and using a viral vector to generate a population of transduced cells. Kaiser fails to teach a population of input cells that comprise at least 80% cells that are CD4+ and/or CD8+ T cells.
Hegazy teaches a method of measuring CD4+ T cells in circulation in the intestine and determined their clonal diversity in addition to assessing phenotypes and effects on resident cell populations. (Pg 1320, Methods) The method involves use of leukoreduction chambers to isolate leucocytes, of which T cells are part of, and then uses magnetic bead separation to isolate a population of purified CD4+ CD154+ T cells. (Pg 1321, Materials and Methods) It is known in the art that CD4+ T cells express CD154 on the surface of the cell. The purified population is then subjected to a variety of tests, including a carboxy-fluorescein succinimidyl ester dilution assay (Pg 1323, Materials and Methods) In addition to this over 60% of the isolated CD4+ T cells expressed high levels of CCR7, with “the majority” of said CD4+ CD154+ T cells co-expressing a combination of CCR7, CCR4, CD161, and CCR6. (Pg 1325-1326, Results) This reads on use of an input population comprising at least 80% or higher CD4+ T cells.
Regarding Claims 5 and 68: Kaiser teaches an embodiment of the invention expressing CCR7. (Pg 4, lines 9-13) Kaiser also teaches a method of production for a “substantially pure cell composition of genetically modified T cells” and defines “substantially pure” as at least 90% or 95% genetically modified T cells. (Pg 20, lines 18-22) This reads on the claimed method of a population of CCR7+ primary T cells of at least 60% purity. Furthermore, Hegazy teaches that the leukoreduction-processed CD4+ T cells have at least 60% CCR7 expression. (Pg 1325, Results)
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Hegazy of an isolation method for a population of CD4+ T cells with the activation method as taught by Kaiser to generate a population of transduced cells that used an input population of CD4+ T cells. One of ordinary skill in the art would have been motivated to use the isolated population of CD4+ T cells as taught by Hegazy due to the cell population having a naturally occurring high percentage of CCR7 expression, making the cell population ideal as an input population for increasing transduction frequency of CCCR7.
Regarding Claim 8: Kaiser defines “providing a cell sample” as one preferentially of hematologic origin, specifically from whole blood, buffy coat, leukapheresis, PBMCs, or any clinical sampling of blood product. (Pg 16, lines 9-13)
Regarding Claim 16: Kaiser teaches that magnetic separation of the T cells of the claimed invention using CD3, CD4, and/or CD8 cell surface markers (pg 4, lines 9-13) and that a “substantially pure cell composition of genetically modified T cells” is defined as at least 90% or 95%, which reads on the claimed method of the T cell population comprising at least 80% of CD3+, CD4+, and/or CD8+ T cells.
Regarding Claim 17 and 50: Kaiser teaches that the “activation” of the T cells of the claimed invention is performed using cell densities between 4e6 cells/mL to 1e7 cells/mL. (Pg 5, lines 20-24)
Regarding Claim 19: Kaiser teaches that the claimed invention is able to generate a “large number of highly viable T cells…over less than 2 weeks” (Pg 3, lines 20-21 and Fig 6 (pg 34) and Fig 8 (pg 36))
Regarding Claims 21 and 23: Kaiser teaches an embodiment of the invention where after the initial enrichment of T cells (which includes genetically modified T cells) a second enrichment step may be carried out with antigen-binding molecules specific for a TCR. (Pg 12, lines 7-16) Kaiser also teaches that the cells of the claimed invention may also be genetically modified to express a CAR, TCR, or any accessory molecule on their cell surface. (Pg 6, lines 3-5) These accessory molecules include antigen-binding molecules for CD3 and CD28, and a preferred embodiment is given of anti-CD3 and anti-CD28 antibodies or fragments thereof. (Pg 4, lines 10-17) This reads on the claimed method of the stimulatory reagent comprising a primary agent binding to the TCR complex and a secondary agent binding to a T cell costimulatory molecule, specifically anti-CD3 and anti-CD28.
Regarding Claim 24: Kaiser teaches an embodiment of the invention where the modulatory agents (such as agonistic antibodies or cytokines) are preferentially coupled to beads or nanostructures. (pg 44, lines 14-20) This reads on the claimed method of having the primary and/or secondary agent present on the surface of a solid support.
Regarding Claim 35: Kaiser teaches that the composition of genetically modified T cells may be administered as a pharmaceutical composition which may comprise adjuvants such as aluminum hydroxide. (Pg 21, lines 23-33) This reads on the claimed method of contacting the composition during at least a portion of the incubating with a transduction adjuvant.
Regarding Claim 43: Kaiser teaches a preferred embodiment of the invention in which transduction of the T cells is carried out with lentiviruses. (Pg 4, lines 29-33)
Regarding Claims 55 and 56: Kaiser teaches that the CARs of the claimed invention can be genetically modified by recombinant methods to express peptides or proteins, for example CARs. (Pg 20-21, lines 27-1) and an embodiment of the invention wherein a second separation step may be performed for recombinantly expressed CAR or TCR on the cell surface of the genetically modified T cell. (Pg 12, lines 7-16)
Regarding Claim 68: Kaiser teaches that preferentially, said genetic modification of the T cells of the claimed invention may be performed by transducing cells with lentiviral vectors (pg 5, lines 3-4) and an embodiment of the invention expressing CCR7. (Pg 4, lines 9-13) Kaiser also teaches a method of production for a “substantially pure cell composition of genetically modified T cells” and defines “substantially pure” as at least 90% or 95% genetically modified T cells. (Pg 20, lines 18-22) This reads on the claimed method of at least 95% of the T cells transduced with the heterologous polynucleotide are CCR7+.
Regarding Claim 71: Kaiser teaches that an automated culture process to create genetically modified T cells results in better transduction efficiency and robust manufacturing of said T cells. (Pg 2, lines 4-11. This reads on the claimed method of being carried out in vitro.
Regarding Claims 72 and 73: Kaiser teaches an example of the claimed invention wherein after transfection and expansion of the genetically modified T cells, the cells are washed with a solution suitable for human infusion and harvested for either direct infusion or for cryopreservation. (Pg 23, “Example 2”) It would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that in order for the T cells to be successfully cryopreserved, a cryopreservant must be added to the composition to ensure the viability of the cells upon thawing. This reads on the claimed method of 73, wherein the composition further comprises a cryopreservant.
Claims 26-28 are rejected under 35 U.S.C. 103 as being unpatentable over Kaiser et al. (WO 2015/162211 A1) in view of Cantor et al. (US 6,027,390 B1) and Schmidt et al. (US 10,065,996 B2)
The teachings of Kaiser and Hegazy are described above. Kaiser teaches a method for automated generation of genetically modified T cells (pg 1, line 5) but both Kaizer and Hegazy fail to teach sequences matching SEQ ID NO. 34 and 36 in addition to use of streptavidin and/or streptavidin mutein.
Cantor et al. teaches methods of use for recombinant streptavidin proteins with a reduced affinity for biotin and use of reduced-affinity streptavidin regarding nucleic acids. (Pg 10, col 1, ln 18-24)
Schmidt et al. teaches various novel streptavidin muteins with specific binding affinities based on the modified amino acids present in the sequence compositions. (Pg 1, Abstract)
Regarding Claim 26: Kaiser teaches an embodiment of the invention where after the initial enrichment of T cells (which includes genetically modified T cells) a second enrichment step may be carried out with antigen-binding molecules specific for a TCR. (Pg 12, lines 7-16) Kaiser also teaches that the antibodies may be used with oligomers, and gives an example of use of a soluble StrepTacin protein oligomer which allows for reversible and modular binding abilities. (Pg 18, lines 10-23) Kaiser fails to teach use of streptavidin or streptavidin mutein molecules.
Schmidt et al. teaches various compositions of streptavidin muteins (pg 1, Abstract) modified to target specific receptor molecules on the cell surface. (Pg 16, col 1, lines 28-34) It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine use of streptavidin mutein proteins with the T cell enrichment process taught by Kaiser to create a stimulatory reagent comprising a soluble oligomeric particle reagent comprising streptavidin or streptavidin mutein molecules with the primary and secondary agents being reversibly bound on the surface of the oligomeric particle reagent. One would have been motivated to do so based on the teachings of Schmidt, who states that short peptide affinity tags (such as streptavidin or streptavidin mutein) have become indispensable for affinity purification and detection assays without the need for any prior knowledge of its biochemical properties. (Pg 16, col 1, lines 38-42) One would have had a reasonable expectation of success due to the examples given both by Schmidt of generation of various streptavidin mutein compositions (Pg 25-33, Examples) and the enrichment and culture process taught by Kaiser. (Pg 3-4, lines 29-7)
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Regarding Claim 27: Cantor et al. teaches a sequence which is 100% identical to SEQ ID NO. 34. See SEQ ID NO. 5 below (pg 19-20, lines 22-11):
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Regarding Claim 28: Schmidt teaches novel streptavidin muteins which have binding affinity for peptide ligands such as biotin, iminobiotin, and thiobiotin (pg 21, col 11, lines 1-7) and teaches a sequence which is 100% identical to SEQ ID NO. 36 of the claimed invention. See SEQ ID NO. 113 below (pg 75, bottom half of page):
Claim 32 is rejected under 35 U.S.C. 103 as being unpatentable over Kaiser et al. (WO 2015/162211 A1) in view of Yan et al. (Spinoculation Enhances HBV Infection in NTCP-Reconstituted Hepatocytes, 2015)
The teachings of Kaiser and Hegazy are discussed above.
Yan et al. teaches that spinoculation is widely used to increase the in vitro infectivity of viruses which results in increased deposition of virions on the cell surface. (Pg 2, second full paragraph)
Regarding Claim 32: Kaiser fails to teach use of spinoculation in the claimed protocol for automated T cell culture. Yan et al. teaches that spinoculation is used to increase the infectivity of viruses by means of increasing the virions deposited on the cell surface (pg 2, second full paragraph) and a protocol to carry out spinoculation-mediated HBV infection on HepG2-NTCP12 cells. (Pg 4, HBV Infection and spinoculation) This reads on the claimed method of spinoculating the viral vector particles with the input population or the stimulated composition.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the culture protocol detailed by Kaiser with the spinoculation technique taught by Yan to create a genetically modified population of CCR7+ expressing T cells subjected to spinoculation to perform the CCR7 transfection process. One would have had a reasonable expectation of success and motivation to do so based on the protocol and teachings of Yan, who states that spinoculation results in increased depositions of virions on the cell surface, thereby increasing the in vitro infectivity of the virus.
Claims 45-48 are rejected under 35 U.S.C. 103 as being unpatentable over Kaiser et al. (WO 2015/162211 A1) in view of Merten et al. (Viral Vectors for Gene Therapy, 2011)
The teachings of Kaiser and Hegazy are described above. Both fail to teach use of a viral envelope glycoprotein and fails to teach a multiplicity of infection (MOI) of between about 1.0 IU/cell to 20 IU/cell.
Merten et al. teaches multiple types and uses of viral vectors, along with example protocols detailing their uses. (Chapters 1-18, pages 1-458)
Regarding Claims 45-46: Kaiser fails to teach use of a VSVG viral envelope glycoprotein. Merten teaches a method of transduction of a Ba-CAG-EGFP/WPRE virus into vertebrate cells using a baculovirus. (Pg 295) Merten specifies that use of a recombinant baculovirus having a VSVG envelope protein modification may increase transduction efficacy to the cells. (Pg 298, no. 31) This reads on the claimed method of use of a glycoprotein envelope, specifically a VSVG.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the protocol taught by Kaiser of producing a population of CCR7+ T cells with use of a VSVG envelope protein as taught by Merten. One would have had motivation and a reasonable expectation of success at doing so based on the teachings of Merten, who states that use of VSVG envelope proteins may increase transduction efficacy.
Regarding Claims 47-48: Kaiser fails to specify a MOI between 1.0 IU/cell to 20 IU/cell. Merten et al. teaches that routine use of a low MOI is beneficial in protein production as it allows the cells to divide several times prior to infection. Specifically, Merten teaches that a MOI of 0.1-1 is beneficial in protein production. (Pg 297, no. 15) This reads on the claimed method of use of a MOI of less than about 20.0 or less than about 10.0 (Claim 47) and also a MOI of about 1.0-10. (Claim 48)
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the culture protocol as taught by Kaiser with the specified MOI taught by Merten during the inoculation step of the claimed invention. One would have had a reasonable expectation of success and motivation at doing so due to the teaching of Merten, who states that a low MOI of 0.1-1 is beneficial in protein production.
Response to Arguments
Applicant's arguments filed 09/08/2025 have been fully considered but they are not persuasive for the following reasons:
Applicant argues that Kaiser fails to disclose an input population of cells that are at least 80% CD4+ and/or CD8+, and has amended claims 1-5 to require this limitation. It is correct that Kaiser alone fails to disclose this teaching, but as necessitated by amendment, Hegazy teaches a population of CD4+ T cells which were isolated by leukoreduction from donors, as disclosed above. This population also comprises over 60% of cells which express CCR7, which would give a person of ordinary skill in the art motivation to use the population as taught by Hegazy in the protocol as taught by Kaiser as the input population of cells.
Applicant argues that Kaiser fails to provide motive to select CCR7 out of the given markers, and claims that CCR7 is only given as an alternative marker. This is incorrect for two reasons:
Firstly, per MPEM 2131.03, "A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396. Specifically, the teachings of Kaiser are directed towards a small, defined genus of markers including CCR7, and it would be equally obvious to a person of ordinary skill in the art to choose any of them.
Secondly, the teachings of Hegazy state that the isolated population of CD4+ T cells also express CCR7 at a rate of over 60% per the population, as discussed above. As this is a relatively high percentage of expression in the input population, this would give a person skilled in the art motivation to select CCR7 from the options provided by Kaiser, as use of a cell population with a high percentage of the desired marker as the input population would result in higher yield after following the protocol as taught by Kaiser.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., transduction variability, CCR7 expression being highly variable, and CCR7 having a greater susceptibility to transduction) 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).
For the above reasons, the arguments provided by the Applicant are unpersuasive and the rejections are upheld.
Conclusion
Applicant’s amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee 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 HANNA M THUESON whose telephone number is (571) 272-3680. The examiner can normally be reached M-F 7:30-5 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.
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/HANNA MARIE THUESON/ Examiner, Art Unit 1638
/Tracy Vivlemore/ Supervisory Primary Examiner, Art Unit 1638