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 Status
Claims 1-21 are pending.
Claims 14-21 are withdrawn.
Claims 1-13 are under examination.
Election/Restrictions
Applicant’s election without traverse of the following invention
Invention
Group I, claims 1-13, drawn to a method for rapid manufacture of a genetically modified T-cell population, in the reply filed on 3rd, August, 2026 is acknowledged.
The requirement is still deemed proper and is therefore made FINAL.
Claims 14-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claim Objections
Claims 3 and 5 are objected to because of the following informalities:
Claim 3 recites “exposing the mixed mononuclear cells to the T-cell activation agent selected from one or more of the group of cytokines consisting of” which is grammatically improper and is missing a to be verb between the “agent” and “selected.”
This objection could be overcome by amending to “the T-cell activation agent, where the T-cell activation agent is selected from one or more of the group of cytokines consisting of IL-2, IL-7, IL-15, IL-12, IL-18, and IL21”
Claim 5 recites “the mononuclear cell population.” While it is clear this intends to refer back to “the mixed mononuclear cell population” recited in claim 1, upon which claim 5 depends, to be consistent as well as to improve the clarity and readability of the claims, it is recommended that Applicant amend to “the mixed mononuclear cell population” in claim 5.
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 1-13 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.
Claims 1 and 14 recites the phrase of “substantially simultaneously” which renders the claim indefinite for several reasons. First, the phrase includes the subjective terminology “substantially.” Therefore the scope of the claim is unclear. A claim may be rendered indefinite by reference to subjective term (see MPEP 2173.05(b), IV). The term “substantially” is not defined by the claim, the specification does not provide a standard for some standard for measuring the scope of the phrase, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Furthermore, claims 1 and 14 are also indefinite because the phrase “substantially simultaneously” includes substantially, which indicates a possible range, together with “simultaneously,” which has a plain an ordinary meaning of “at the same time.” It is unclear how a timing can be “at the same time” (the claimed “simultaneously”) while also not being at the same time (the claimed “substantially” which implies some amount of range of variation. Therefore, the metes and bounds of the phrase “substantially simultaneously” are unclear and the scope of the claim is indefinite.
By nature of their ultimate dependency on claim 1, claims 2-13 are also rejected because they do not clarify the issue.
Claim 2 recites “the steps of simultaneously activating and exposing to at least one viral vector,” However claim 1, upon which claim 2 depends, does not recite a method of “simultaneously activating and exposing” and instead recites the indefinite phrase of “substantially simultaneously” discussed above. Therefore, there is improper antecedent basis for this term, and the metes and bounds of the breadth of what the “steps of simultaneously activating and exposing” encompass is unclear.
Claim 2 recites “exposing to at least one viral vector” However claim 1, upon which claim 2 depends, does not recite “exposing to at least one viral vector” and instead recites “a viral vector”. Therefore, there is improper antecedent basis for this term, and the metes and bounds of the breadth of what the “at least one viral vector” encompass is unclear because it is unclear whether additional structural elements of additional vectors other than “a vector” are intended to be encompassed by the claim and it is unclear what the structural elements of these potential additional vectors encompass.
Claim 3 is vague and indefinite in the use of parenthesis, since it is unclear whether the parenthetical material is or is not intended to be part of the claim.
Generally, when the claims are indefinite, vague or unclear, they cannot be construed without speculation or conjecture; therefore, the indefinite claims are not treated on the merits with respect to prior art. See In re Steele, 305 F.2d 859, 862 (CCPA 1962) (A prior art rejection cannot be sustained if the hypothetical person of ordinary skill in the art would have to make speculative assumptions concerning the meaning of claim language.); see also In re Wilson, 424 F.2d 1382, 1385 (CCPA 1970) ("If no reasonably definite meaning can be ascribed to certain terms in the claim, the subject matter does not become obvious-the claim becomes indefinite."). Notwithstanding Steele, the Office has made every attempt to construe the claims in what the Office believes is the intent of the Applicants in the interest of compact prosecution.
Claim 13 recites “a step of differential centrifugation following the step of substantially simultaneously activating and exposing to the viral transduction vector to remove a plasmid DNA from genomic DNA by DNA size selection.” The scope of claim 13 is indefinite because there is no nexus between the differential centrifugation step recited in claim 13 and the preamble of claim 1, upon which claim 13 depends, of “a method for rapid manufacture of a genetically modified T-cell population.” In other words, it is unclear how the method steps of claim 13 are integrated into the method of claim 1 because they appear to be drawn to unrelated method steps of sample processing and there is no link between these steps and the method of claim 1.
Claim Interpretation
Due to the 112b issues identified above, for the sake of compact prosecution, the claims identified with 112 issues above are being examined against the prior art and double-patenting as follows:
As set forth above, claim 1 recites the indefinite phrase “substantially simultaneously.” The instant specification does not specifically define “substantially” or “simultaneously.”
The instant specification teaches activation of T cells at Day 0 and cell transduction at Day 0 where viral vector is added to PBMCs “immediately after addition of the T cell activation” (para. [0079]). Because the specific Ioan does not provide a special definition for immediately, and because adding a composition takes some amount of time, it is given its plain and ordinary meaning of very close to something. Therefore, in light of the specification, for the purposes of being examined against the prior art and double-patenting, the indefinite phrase of “substantially simultaneously” in interpreted to mean that the viral vector is added at the same time as or a short amount of time after the T cell activation.
Therefore, the pending claims have been "given their broadest reasonable interpretation consistent with the specification." (In re Hyatt, 211 F.3d1367, 1372, 54 USPQ2d 1664, 1667 (Fed. Cir. 2000); see MPEP 2111).
Claim Rejections - 35 USC § 102
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.
Claims 1-12 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Frost et al. (WO-2020047527-A2; published on 5th, March, 2020; henceforth “Frost”).
Regarding claim 1, Frost discloses a method for rapid (in Example 4, incubation times from 1 minute to 4 hours were tested and “the ability of each of the recombinant lentiviral particles to transduce PBMCs was similar across all incubation periods” para. [0520] and the method therefore the shorter incubation times are encompassed by the broadest reasons bale interpretation of “rapid” as claimed) manufacture of a genetically modified T-cell population (“methods and compositions for genetically modifying lymphocytes, for example T cells” abstract; see also para. [0010]), comprising: obtaining a mixed mononuclear cell population (“enriched PBMCs or transduction reactions without prior PBMC enrichment” para. [0012]; see also para. [0014, 0017-0018, 0059, 0067-0074, 0089-0091, 0096-0098, 0100-0104, 0109, 0111, 0113, 0115, 0123, 0220, 0283, 0285, 0287-0288, 0299, 0303, 0335, 0418-0419, 0438, 0448, 0450-0455, 0459, 0462, 0465-0466, 0468, 0496, 0507, 0510-0521, 0526, 0528-0530, 0538-0541, 0543-547, 0550]; claim 15; Example 2; Figures 1A-1B, 4A-B, 5);
and simultaneously (“pre-activation of the T cell and/or NK cell is not required, and an activation element, which can be any activation element provided herein, is present in a reaction mixture in which the contacting takes place” and “the activation element is present on a surface of the replication incompetent recombinant retroviral particle” para. [0067] and therefore the exposure is simultaneous) exposing a T-cell population comprised in the mixed mononuclear cell population (PBMCs contain T-cells) to a T-cell activation agent (“activation element” para. [0067]); and exposing the mixed mononuclear cell population to a viral vector adapted to transduce at least the T-cell population comprised in the mixed mononuclear cell population with a foreign nucleotide (“polynucleotide provided by the replication incompetent recombinant retroviral particles” para. [0193]; “a plasmid encoding UCHTlscFvFc-GPI” Examples 2 and 4) (“contacting the lymphocyte with a (typically a population of) replication incompetent recombinant retroviral particle, wherein the replication incompetent recombinant retroviral particle typically comprises a pseudotyping element on its surface, wherein said contacting (and incubation under contacting conditions) facilitates membrane association, membrane fusion, and optionally transduction of the resting T cell and/or NK cell by the replication incompetent recombinant retroviral particle, thereby producing the genetically modified T cell and/or NK cell” para. [0067]; see in particular Examples 2-4).
Furthermore, regarding the preamble of claim 1, the preamble merely states, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, and therefore the preamble is not considered a limitation and is of no significance to claim construction (see MPEP 2111.02) See also Rowe v. Dror, 112 F.3d 473, 478, 42 USPQ2d 1550, 1553 (Fed. Cir. 1997) ("where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation"). As set forth above, Frost discloses all the required structural elements of the structurally complete invention in the claim body and therefore meets instant claims.
Regarding claim 2, further to the discussion of claim 1 above, Frost discloses a step of harvesting the mixed mononuclear cell population comprising at least a genetically modified T-cell population at up to 24 hours from the steps of simultaneously activating and exposing to at least one viral vector (“this entire method/process from blood draw from a subject to reintroduction of blood back into the subject after ex vivo transduction of T cells and/or NK cells, in non-limiting illustrative embodiments of any aspects provided herein, can occur over a time period less than” and embodiment of “less than 24 hours, less than 12 hours, less than 11 hours, less than 10 hours, less than 9 hours, less than 8 hours, less than 7 hours, less than 6 hours, less than 5 hours, less than 4 hours, less than 3 hours, 2 hours, or less than 2 hours” which include harvesting up to 24 hours from the steps (para. [0126]).
Regarding claim 3, further to the discussion of claim 1 above, Frost discloses the T-cell activation agent is one or more of activators for CD3, CD28, OX40, ICOS or 4-1BB (para. [0336]) (“the activation element is anti-CD3, such as anti-CD3 scFv, or anti-CD3 scFvFc” para. [0067]; see also “an anti-CD3 associated with a surface of the replication incompetent retroviral particle” para. [0095]; para. [0110, 0486]; see in particular “ACTIVATION ELEMENTS” para. [0332-0352]).
Regarding claims 3-4, further to the discussion of claim 1 above, Frost discloses that the activation is performed by exposing the mixed mononuclear cells to a T-Cell activation agent that is a cytokine (“replication incompetent recombinant retroviral particles have a membrane-bound cytokine fusion polypeptide on their surface that is capable of binding a T cell and/or NK cell and promoting proliferation and/or survival thereof” para. [0353]) that is IL-2 (instant claims 3-4) IL-7 or IL-15 (instant claim 4) (“the cytokine fusion polypeptide includes IL-2, IL-7, IL-15” para. [0354]).
Regarding claim 5, further to the discussion of claim 1 above, Frost discloses a step of at least partial depletion by adherence of a monocyte population comprised in the mononuclear cell population prior to the steps of activating and exposing to the viral vector (“the T cells and/or NK cells have been incubated overnight on an adherent substrate to remove monocytes before the transduction” para. [0121]).
Regarding claim 6, further to the discussion of claim 1 above, Frost discloses the steps of activating and exposing to the viral vector are performed in the absence of any exogenous cytokine (“No exogenous cytokines were added to the samples at any time” para. [0510]).
Regarding claims 7-8, further to the discussion of claims 1 and 6 above, Frost discloses the step of activating is performed by exposing the mixed mononuclear cell population to one or both of a CD3 activator or a soluble or surface-bound CD3 antibody (“the activation element is anti-CD3, such as anti-CD3 scFv, or anti-CD3 scFvFc” para. [0067]; see also “an anti-CD3 associated with a surface of the replication incompetent retroviral particle” para. [0095]; para. [0110, 0486]; see in particular “ACTIVATION ELEMENTS” para. [0332-0352]).
Regarding claim 9, further to the discussion of claim 1 above, Frost discloses the steps of activating and exposing to the viral vector are performed without a prior T-cell isolation (“transduction reactions of enriched PBMCs or transduction reactions without prior PBMC enrichment, such as in whole blood” para. [0012]; see also Examples 2-4 which perform these steps on PBMCs and T cells have not been isolated) or pre-activation step (“pre-activation of the T cell and/or NK cell is not required” para. [0067]; see also Examples 2-4 which do not have a pre-activation step).
Regarding claim 10, further to the discussion of claim 1 above, Frost discloses cryopreserving the mixed mononuclear cell population comprising the genetically modified T-cell population (“the final product typically in an infusion bag for reinfusion or cryopreservation vial for storage” para. [0089]; see also para. [0094]; Figures 1A-B).
Regarding claim 11, further to the discussion of claim 1 above, Frost discloses obtaining the mixed mononuclear cell population by apheresis (para. [0096, 0103-0104]) or a peripheral blood draw (para. [0126-0127, 0130])
Regarding claim 12, further to the discussion of claim 1 above, Frost discloses the viral transduction vector is a lentivirus, a retrovirus (para. [0010, 0117-0118, 0054, 0069, 0076, 0097, 0107, 0220, 0249, 0283, 0289, 0292, 0302, 0328, 0332, 0366, 0369, 0371, 0378-0382, 0385, 0419, 0491, 0502-0504, 0506, 0514-0515, 0517-0521, 0523, 0525, 0526-0527, 0534, 0537, 0539, 0542-0543]; Examples 1-2, 4; claim 40), or an adenovirus (para. [0380, 0387, 0418]) and therefore the step of selecting the viral transduction vector from the group consisting of a lentivirus, a retrovirus, and an adenovirus has necessarily occurred in the disclosed method because Frost discloses all these options and provides working examples in lentivirus, which is a type of retrovirus (Examples 1-2 and 4).
Accordingly, Frost anticipates instant claims.
Examiner’s Remark
The prior art of Frost et al. (WO-2020047527-A2; published on 5th, March, 2020; henceforth “Frost”) applied above is prior art under both 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) . WO-2020047527-A2 is published 5th, March, 2020 which pre-dates the effective filing date of the instant Application and it is therefore prior art under 35 U.S.C. 102(a)(1). WO-2020047527-A2 is also a WIPO publication by another inventor that designates the United States and was filed 2nd, September, 2019 and claims priority to U. S. Provisional Applications with an earliest effective filing date of 2nd, September, 2018 which is before the effective filing date of the claimed invention and it is therefore prior art under 35 U.S.C. 102(a)(2). To overcome this rejection, Applicant will need to overcome both the rejection 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Frost.
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.
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.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Frost et al. (WO-2020047527-A2; published on 5th, March, 2020; henceforth “Frost”) in view of Sack et al. (G3 (Bethesda) . 2016 Sep 8;6(9):2781-90.; henceforth “Sack”) and Addgene (2018, accessed at: https://www.addgene.org/protocols/purify-plasmid-dna/)
The teachings of Frost above are incorporated herein in their entirety.
Regarding claim 13, further to the discussion of claim 1 above, although Frost teaches isolating genomic DNA from samples and further analyses of transgene expression with qPCR (“Genomic DNA (gDNA) isolated from tissue samples were evaluated for the presence of transduced lymphocytes by bioanalytical qPCR” para. [0542]; see also para. [0503, 0542-0543]), Frost is silent to step of differential centrifugation following the step of activating and exposing to the viral transduction vector to remove plasmid DNA from genomic DNA by DNA size selection.
Nevertheless, regarding claim 13, Addgene teaches a step of differential centrifugation to separate genomic DNA and plasmid DNA (pg. 2 step 6).
Additionally, regarding claim 13, Sack teaches that residual plasmid DNA can contaminate transduced cells and these plasmids serve as additional copies of the PCR template during library amplification, resulting in substantial inaccuracies in measurement (abstract).
Therefore, regarding claim 13, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method of Frost, and combine the known prior art element of the differential centrifugation to separate genomic DNA and plasmid DNA of addgene to obtain the predictable result of separated genomic and plasmid DNA. One of ordinary skill would have been motivated to do so as taught by Sack to reduce residual plasmid DNA and therefore reduce inaccuracies in measurement (abstract). Regarding the reasonable expectation of success, addgene evidences a method step of differential centrifugation to separate genomic DNA and plasmid DNA (pg. 2 step 6).
Hence, the claimed invention as a whole was prima facie obvious.
Conclusion
No claim is allowable.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRIANA N EBBINGHAUS whose telephone number is (703)756-4548. The examiner can normally be reached M-F 9:30 AM to 5:30 PM ET.
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/BRIANA N EBBINGHAUS/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632
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