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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on Mar. 30, 2026 has been entered.
Claim Status
Claims 1, 3, 5, 7-10, 14-17, and 22-33 are currently pending in this application.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-13, in the reply filed on Nov. 22, 2023 is acknowledged. Claims 14-17 and 22-33 are withdrawn for being directed to non-elected subject matter, and claims 1, 3, 5, and 7-10 have been considered on the merits.
Benefit of Priority
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. CN 201810368646.3, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for all the instant claims due to culturing the DC cells in a medium comprising IL2 for as long as 2 months and wherein the method does not comprise a step of isolating DC cells as determined from the English translation (CN108546679A) provided in the PTO-892 form herewith. Additionally, claim 10 lacks adequate support for human telomerase reverse transcriptase (hTERT). Therefore the earliest effective filing date of instant claims 1, 3, 5, and 7-10 is Feb. 20, 2019.
Information Disclosure Statement
The information disclosure statement filed 8/22/22 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each non-patent literature publication or that portion which caused it to be listed and all other information or that portion which caused it to be listed, or alternatively, in the case of only an abstract portion thereof, that the IDS expressly notes only the Abstract in concordance with the reference uploaded. Applicant is advised to either amend the IDS to clarify "Abstract only" or provide a copy of the entire Mahieux, R., et al. (2009) and/or Maraskovsky, E., et al. (1996) references to the Office. While the abstract has been placed in the application file and considered, any information referred to beyond the abstract has not yet been considered. As Mostoller et al. (2004) was considered in its entirety, a copy of the full reference considered by the Office is included herewith and listed on the PTO-892 form.
Claim Objections
Claim 1 recites the phrase “continuing to culture,” which is unclear as to whether there was a previous culturing to continue from (e.g., in a medium comprising IL2), such as during the allowing and/or introducing steps, or if this “continuing” is merely indicating the culturing step occurs subsequent to the contacting step. Appropriate correction is required, such as by removing the term “continuing” as in “culturing the contacted DC cells in a medium...” or alternatively by adding a clarifying limitation requiring a prior culturing.
Claim Interpretation
The preamble of claim 1 “for establishing a pure dendritic cell (DC cell) line” is interpreted as a claim limitation as to the properties of the DC cells produced by performance of the method as this preamble expresses the intentional purpose for why the method is to be performed (see MPEP 2111.02). While the phrase “establishing a pure dendritic cell (DC cell) line” in claim 1 is not defined by the claims or instant application, it is interpreted in view of the prior art as implying the creation of a composition comprising a DC cell, or population of DC cells, that are at least partially purified of other types of cells in the sample (e.g., non-DC individual scattered cells and/or T-cells (see [0159])) as well as encompassing fully pure DC cells, such as determined by DC-specific cell surface markers (see e.g., Lee et al., J Exp Med 212: 385-99 (2015) at Material and Methods; pg. 392, left col., last para., to right col., 1st para.; Fig. 6; Geissmann et al., Nat Rev Immunol 10: 453-60 (2010) at pg. 454, left col., last para., to right col., 3rd para.).
It is noted that in claim 1, the cell sample is interpreted as necessarily being an in vitro composition and thus the contacting (introducing and expressing) is considered as being limited to in vitro. It is also noted that in claim 7 due to the limitations of claim 1, there cannot be any step of isolating DC cells from the sample, such as before, during or after the mononuclear cell isolating or mononuclear cell differentiating steps.
Claim 8 is interpreted as encompassing wherein the mononuclear cells are contacted with both GM-CSF and IL-4, either sequentially or simultaneously.
In claim 9, the term “antigen” is interpreted as encompassing any antigen to any human immune cell regardless of whether naturally occurring or artificial created and independent of any in vivo immune system (i.e., encompassing in vitro antigenicity), for example wherein the antigen is a native hTERT epitope in view of dependent claim 10. It is noted that virtually all proteinaceous moieties having at least 4-8 residues can exhibit some antigenicity in vitro.
Claim Rejections - 35 USC § 112(a), Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3, 5, and 7-10 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement for failing to particularly point out and distinctly claim the subject matter. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claimed invention as a whole is not adequately described if the claims require essential or critical elements that are not adequately described in the specification and that is not conventional in the art as of applicant’s effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing, or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics, Inc., 48 USPQ2d 1641,1646 (1998).
In making a determination of whether the application complies with the written description requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is claiming and what Applicant has possession of. The invention of claim 1 is a method comprising (1) contacting a peripheral or cord blood sample containing human DC cells with a Tax protein expressed by at least a subset of the DC cells comprising a vector expressing said Tax protein, (2) culturing the contacted DC cells in a medium comprising IL-2 for 3 weeks to 2 months; wherein the method does not comprise any isolating of DC cells from the sample.
The preamble of “for establishing a pure” DC cell line is a recited intended purpose/use that limits the claimed methods to be capable of producing a viable DC cell line as well as implying the DC cells produced by the method are “pure” or can be made “pure” without any isolating of DC cells from the sample (e.g., by any “sorting treatment” ([0159)), i.e., the method produces DC cells isolated at some minimum level of purity, including encompassing up to 100% purity.
The instant specification describes such methods prophetically wherein the cells are continued to be cultured in medium comprising IL-2 for 3 weeks to 2 months and the expression of markers are analyzed by FACS to determine the purity of DC cells, including mature and/or activated subsets thereof (Method 1, [0097]; Method 2, [0107]). The application only describes working examples wherein the method produces essentially “pure” cells after 2 months of culturing, i.e., only clumped cells without any scattered cells (Example 2, [0159]). The specification purports without empirical evidence that these DC cell populations are “pure” of non-DC cells, such as contaminating PBMC T cells as well as, e.g., B cells, NK cells, NKT, and hematopoietic stem/progenitor cells.
The claimed method would require converting an initial about 1% subset of PBMC DC cells or less initially present predominantly with T cells (a 65% subset) depending on the sample to 98% or more DC cells (see instant [0158]-[0159]) and without any isolating step or sorting treatment specific for DC cells.
The prior art is silent as to a method of making a human peripheral or cord blood sample into an expressly “pure” DC cell line without a step of isolating a DC cell(s) or stem cell(s) from the sample. Instead, the art teaches making over 95-98% pure in vitro dendritic cell (DC) populations (including ones containing mature DC) using isolating steps, such as magnetic activated cell sorting (MACS) depletion of CD19+ cells and MACS selecting for CD1+, CD141+, or CD134+ and then fluorescent activated cell sorting (FACS) selecting for HLA-DR+, HLA-DR+/BDCA4+ HLA-DR+/CD141+ (and optionally for CD1+) while depleting Lin+ (Lutz et al., Eur J Immunol 53: e2249816 (2022) at pg. 42-46, 2.2.3, Fig. 22). For example, a 2020 STEMCELL® Technologies EasySep® manual only asserts as much as 99% purity of CD14+ monocytes using FACS cell sorting of a peripheral blood leukapheresis sample (Fig. 5c, Fig. 9).
The scope of the term “pure” in the preamble of claim 1 encompasses producing DC cell populations of 100% purity, and the instant written description reports corroboratory that after 2 months of culturing, “pure” DC cells were achieved as proven by various markers and cell morphological analyses ([0159]). Thus, it is not clear from the instant application as to the purity of the DC cells after continuing to culture the DC cells in a medium comprising IL-2 for less than 2 months, such as for exactly 3 weeks or less than 2 months as encompassed by claim 1 as the description notes the scattered cells eventually disappear without precision beyond 2 months as to the timing of this eventuality. Therefore, the skilled artisan cannot envision the full scope of claim 1 for shorter durations than 2 months. Accordingly, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that the applicant is in possession of the full scope of the method of claim 1.
Furthermore, as the only written description support in the instant specification is that after 2 months of culturing, “pure” DC cells were achieved as purportedly proven by various unrecited markers and cell morphological analyses without disclosure of said methodology and results ([0159]), the precise level of purity is still in question. In view of the art it is not predictable that 100% pure DC cell population could have be created in vitro even with any isolating step, such as via positive or negative selection, e.g., via cell sorting enrichment and/or immunodepleting non-DC cell types (e.g., via immunomagnetic depletion via MACS).
The written description fills this silent gap in the conventional arts with a single embodiment purportedly achieving “purity” without disclosure of sufficient detail to satisfy the quid pro quo bargain with the public. With respect to showing possession, the Federal Circuit has emphasized that "the hallmark of written description is disclosure" and the “purpose of the written description requirement is to ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor's contribution to the field of art as described in the patent specification” (Ariad, 598 F.3d at 1351, 1353–54; MPEP 2163.03). For example, description as to how to achieve a necessary Tax protein expression profile to obtain the claimed DC purity in a blood sample even after culturing for 2 months, such via transient transfection or stable viral vector transduction, promoter type (inducible/constitutive) and timing (e.g., induced for one hour, one day, or the entirety of the continued culturing). Instead, the claims merely state “express it” from any expression vector without limitation and even in claim 3, there is no recital of any detail as to a promoter, expression timing, and/or Tax protein dose/dosage minimum for the contacting nor any specific culturing conditions.
Therefore, the skilled artisan cannot envision the full scope of claim 1 for purities of 100% in view of the lack of evidence and the prior art failing to achieve over 100% purity even with multiple cell sorting steps. Instead, the skilled artisan can only envision using approximately the exact method described (but not precisely claimed) to achieve such in the application is followed: which included additional steps such as obtain a peripheral blood sample from a healthy human donor, purifying the peripheral blood sample using centrifugation to obtain a buffy coat sample, culturing the buffy coat cells in a medium comprising serum, PHA factor and IL2 prior to transfection with a STLV3 Tax lentivirus expressing STLV3 protein.
Accordingly, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that the applicant is in possession of the claimed method. The claimed invention as a whole is not adequately described if the claims require essential or critical elements that are not adequately described in the specification and that are not conventional in the art as of applicants effective filing date, such as starting DC cell amount and culture duration minimum to ensure a requisite purity level and/or requiring separating adherent and/or aggregate cells away from other cells (e.g., non-DC scattered cells). While the claims imply the resulting DC cell population is pure, claim 1 as drafted in view of the instant specification and prior art does not predictably ensure any level of purity at 3 weeks, e.g., from sample contaminating T-cells, B cells (e.g. EBV-transformed), NK cells, NKT cells and/or hematopoietic progenitor cells.
Therefore, the skilled artisan cannot envision the full scope of claim 1 for producing a “pure” DC cell population by continuing to culture the DC cells in a medium comprising IL2 for less than 2 months without further evidence due to the instant applications silence as to any duration less than 2 months (e.g., 21-59 days). None of the dependent claims correct this deficiency.
Therefore, the claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventors, at the time the application was filed, had possession of the full scope of the invention as claimed.
35 USC § 112(a) – Scope of Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3, 5, and 7-10 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification while being enabling for wherein the “pure” DC cells are less than 100% pure, or if 100% pure, wherein the blood sample is from healthy human’s peripheral blood that is purified by centrifugation to obtain a PBMC (buffy coat) sample having at least 10 million cells (e.g., 100,000 DC), these purified PBMC are stimulated by culturing with phytohemagglutinin (PHA) factor, cultured for at least 2 days with IL-2 before STVL3 Tax protein contacting, the Tax protein contacting occurs in the presence of IL-2 and the culturing is continued for at least 2 months, the introducing is via stable viral vector transduction/transfection, Tax expression is driven throughout the 2 months of culturing, and the Tax protein consists of SEQ ID NO: 3; does not enable any person skilled in the art, to which it pertains or with which it is most nearly connected to, to perform the claimed methods to produce 100% pure DC cell population without any DC isolating step.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (a)). The court in Wands states that "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue.' Not 'experimentation;" (Wands, 8 USPQ2d 104). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighting many factual considerations." (Wands, 8 USPQ2d 1404).
The factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation required is “undue” include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Furthermore, the USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention:
The claims are directed to methods of creating (1) a pure dendritic cell population from a human peripheral or cord blood sample cultured in vitro without any step of isolating DC cells from the cell sample strain by using (2) an expression vector introduced into DC cells in the sample to express STLV3 Tax protein in DC cells wherein (3) the Tax protein contacted DC cells are cultured in a medium with IL-2 for 3 weeks to 2 months.
Breadth of the claims
The claims are broadly directed to wherein the final purity of DC cells encompasses 100% purity despite no prior evidence of this achievement in the art by any method. The claims are also broad in that the IL-2 culturing duration can be any duration from 3 weeks to 2 months and the number of DC cells present in the sample are unlimited.
The state of the art:
The prior art teaches methods of obtaining almost 95% pure human monocytes from peripheral blood samples (Table 1) and differentiating these cells into DCs (Marques et al., Biol Proced Online 20:4 (2018) at Fig. 2). Post-filing art teaches methods of obtaining 99% pure CD14+ monocytes using both MACS depletion and FACS cell sorting of a peripheral blood leukapheresis sample which can then be differentiated into DCs (STEMCELL® Technologies EasySep® manual at Fig. 5c, Fig. 9).
However the prior art is silent as to any method of converting a human donor’s blood sample into 100% pure DC cells without any step of isolating DC cells from the sample. Thus, this aspect must be shown to a reasonable extent over the scope of said strains of any mammal species so that one of the ordinary skills in the art would be able to practice the invention without any undue or unreasonable burden being on such an Artisan.
The amount of direction and guidance and working examples provided by Applicant:
Such unpredictability in the art can be made more predictable with empirical evidence, such as evidence of working embodiments of claim 1. The instant application provides only a single working example wherein the method purported to achieve 100% purity comprised obtaining a peripheral blood sample from a healthy human donor, purifying the peripheral blood sample using centrifugation to obtain a buffy coat sample (PBMCs), washing the PBMCs with PBS, culturing the PBMCs in a medium and stimulating with PHA factor and IL-2 prior to STLV3 protein expression including at least 2 days of culturing with IL-2, using a single Tax protein species consisting of SEQ ID NO: 3, and continuing to culture for 2 months to achieve said “pure” results, i.e., 100% DC purity.
Furthermore, as the only working embodiment disclosed in the instant specification is that after 2 months of culturing, “pure” DC cells were achieved as purportedly proven by various unrecited markers and cell morphological analyses without disclosure of said methodology and results ([0159]), the precise level of achieved purity is still in question. In view of the art it is not predictable that 100% pure DC cell population could have be created in vitro even with any isolating step, such as via positive or negative selection, e.g., via cell sorting enrichment and/or immunodepleting non-DC cell types (e.g., via immunomagnetic depletion via MACS). Therefore, the skilled artisan does not have clear guidance in achieving 100% purities when deviating from this single working embodiment in view of the lack of guidance as to the methodology to determine such purity result, the lack of evidence about this result, and the prior art failing to achieve over 100% purity even with multiple cell sorting steps.
The instant application lacks guidance regarding the high generality of the method steps recited in the instant claims. For example, how to achieve a necessary Tax protein expression profile to obtain DC purity in a blood sample, such via transient transfection or stable viral vector transduction, promoter type (inducible/constitutive) and timing (e.g., induced for one hour, one day, or the entirety of the continued culturing). Instead, the claims merely state “express it” from any expression vector without limitation and even in claim 3, there is no recital of any detail as to a promoter, expression timing, and/or Tax protein dose/dosage minimum for the contacting. In particular, the total number of cells and tax expression efficiency could be critical as well as the precise technique to exchange media impacting scattered cell removal. For example, EVB-transformed B cells are known to occur at some frequency over time in cultured ex vivo blood cell samples from among EBV-seropositive donors and such immortalized cells can out expand other cell types in the culture stressing the importance of using healthy donor samples (see Ahmed et al., Cancers 15: 3046 (2023) at abstract, pg. 2, Fig. 2 and 5).
In the working example, the peripheral blood sample (7-9 mL) has an estimated 10 million mononuclear cells total and thus, an estimated 100,000 DC cells. As lower starting cell densities in cultures prolong non-exponential growth times and require more doublings to reach the same cell densities as higher starting cell densities, the purity obtain is likely altered significantly by the number of DC cells and/or DC progenitor cells present upon the contacting and/or culturing steps. However no where do the claims account for this and written specification guidance is only provided with the combination of 2 months for a sample with ten of thousands of DC cells.
Regarding claims 7-8, the instant specification lacks a working example of any method comprising differentiating mononuclear cells into DC cells and achieving 100% purity of DC cells at the end of the method.
The quantity of experimentation needed to make and/or use the invention:
Extensive experimentation would be required to determine how to create a 100% pure DC cell from blood sample cells in the absence of any DC isolating step. The field of DC cell expansion in culture in the presence of other mononuclear cells has not evolved such that, without guidance or working examples in the specification, the artisan could predictably perform the method of claim 1 without undue and/or unreasonable experimentation when deviating from the single working example regarding crucial elements.
Given the lack of working examples, the limited guidance provided in the specification, the lack of guidance in the prior art, and the broad scope of the claims with regard to purity and culture conditions, undue and unreasonable experimentation would have been required for one skilled in the art to use the claimed methods to produce the recited result of 100% purity across the breadth of 3 weeks to 2 months of culturing, which may never be achievable at all.
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, 3, 5, and 7-10 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the relative term “pure” with regard to a dendritic cell (DC cell) population, which is interpreted herein as being at least partially pure regarding non-DC cell types of cells as typically observed in the art as well as encompassing 100% pure DC cells. However this relative term renders the claim indefinite because neither the claim nor the specification provides a definition or standard for the “purity” level satisfying “pure” and, thus, one of ordinary skill in the art would not be reasonably appraised of the scope of this limitation (see MPEP 2173.05(b)). It is appreciated in the art that a DC population obtained from in vitro culture of PBMCs over 3 weeks or longer having not undergone any cell isolating procedure is likely to be less than 100% pure (e.g., at most 98%, 99%, or 99.9% pure). To the extent applicant wants to argue a contrarian scope of the interpretation of this term, see the 112(a) rejection above. Claims 3, 5, and 7-10 are included in this rejection for depending from indefinite claim 1.
Claim 1 recites wherein “the method does not comprise a step of isolating the DC cells from the cell sample,” which is ambiguous and unclear both as to what “the DC cells” and “the cell sample” refer to. In the method as claimed, “the cell sample” is contacted with a Tax protein and cultured for 3 weeks to 2 months. Does “the cell sample” stop being “the cell sample” upon the contacting step, upon the continuing to culture step, or at some point during culturing for 3 weeks to 2 months? In other words, does the “no isolating” negative limitation apply throughout the method, only to “the cell sample” provided to the contacting step, or something in between. Similarly, does the “no isolating” negative limitation apply to the DC cells produced by the contacting step and/or continue to culture step as well as to the resulting DC cell(s) after performance of all recited method steps for establishing the “pure” DC cell line?
Claim 7 depends from “the method of claim 6” but claim 6 was canceled rendering claim 7 indefinite. All the limitations of claim 6 needs to be recited in claim 7 and not merely by reference to a canceled claim. Because claims 7 and 8 depend from a canceled claim, the metes and bounds of each of claims 7 and 8 cannot be determined for the purposes of applying prior art.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, and 7-10 are rejected under 35 U.S.C. 103 as being unpatentable over Cheng3 (WO2017070237A1, published 2017-4-27, priority to 2016-10-19; IDS ref.) in view of Mahieux (Mahieux and Gessain, Viruses 3: 1074-90 (2011)).
The claims are interpreted as provided in a previous section.
Cheng3 teaches methods of contacting a human peripheral blood cell sample (PBMCs) containing dendritic cells (DC or DCs) with a T cell leukemia virus Tax protein via expression from a viral expression vector introduced into the DC cells via transduction or transfection and continuing to culture the DC cells in a medium comprising IL-2 (e.g., (100-200 U/mL) for 3 weeks or as long as 2-3 months, such as to immortalize and activate the blood DCs by the Tax protein’s ability to promote DC maturation and activation following a phytohemagglutinin (PHA) treatment (pg. 7-10, 24-27, 30-31, 40-43, 70-71, and 75-77; pg. 56-60 at 62-63, 68, 70-71, 73, 79-80, 118-120, 125, and 130). Although Cheng3 notes that for some embodiments of the methods, T cells are depleted from a sample, this is never strictly required by any description of such methods.
Regarding claim 1, Cheng3 does not teach wherein the T cell leukemia virus Tax protein is an STLV3 Tax protein, instead teaching using HTLV Tax proteins, such as HTLV-3 (pg. 32, last para., to pg. 33, line 1; pg. 43, last para., to pg. 44, line 1; pg. 5, line 25-26; pg. 8, line 25-26; pg. 24, last para.) or variants thereof (pg. 26, last para.; pg. 25, para. 4).
However Mahieux teaches HTLVs belong to the primate T lymphotropic virus group (PTVL), which also includes simian STLV counterparts like STLV3 (Abstract; pg. 1075, 1st para.), which infects both non-human primates and humans (Table 1; pg. 1080, last para.). Moreover Mahieux teaches the PTLV-3 subgroup comprises STLV-3, which is a homologous strain to HTLV-3 and they share 87 to 99% sequence identity depending on the strain analyzed (pg. 1077, last para., to pg. 1081; Fig. 2, Table 1; pg. 1082, 3rd para).
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to perform a method of Cheng3 of making activated and mature DC cells by stimulating DC cells of a human blood sample with a viral vector expressing a Tax protein wherein the Tax protein is an STLV3 Tax protein instead of an HTLV3 Tax protein. One of ordinary skill in the art would be motivated to investigate simian HTLV counterparts in a human cell context as Mahieux teaches HTLV-3 viruses may have originated via zoonotic reservoirs allowing interspecies transmission of STLV-3 to infect human cells (pg. 1080-1081), such as to confirm conservation of Tax protein characteristics in DC maturation and activation as already known for HTLV-3 Tax from Cheng3.
Regarding the duration of 3 weeks to 2 months recited in the claim, a prima facie case of obviousness exists where claimed ranges overlap prior art disclosed values or ranges (MPEP 2144.05). Although Cheng3 does not teach any specific purity of DC cells achieved over the 3 weeks to 2 months of culturing, by the logic of claim 1 as written, the cell population produced by the same active method steps inherently has the required properties for establishing a pure dendritic cell line in the absence of evidence to the contrary. To the extent Applicant argues otherwise, see the 112(a) rejections above.
Regarding claim 3, Cheng3 teaches wherein the viral vector is a lentiviral vector introduced into the DC cells by transduction (pg. 65, 2nd para.; pg. 75, line 28, to pg. 77, line 6).
Regarding claim 7, Cheng3 teaches wherein the DCs are obtained by differentiating isolated mononuclear cells from a human blood sample (pg. 7, 10 and 24).
Regarding claim 8, Cheng3 teaches wherein the mononuclear cells are contacted with PHA and IL-2 or GM-CSF and IL-4 (pg. 71, 7, 31, and 55 at 62; pg. 10, 40, 43, and 59 at 118, last line of pg. 23 to first line of pg. 24).
Regarding claims 9-10, Cheng3 teaches introducing an expression vector expressing a tumor-associated antigen, such as hTERT (pg. 20, last pare.; Fig. 5; pg. 67).
Claims 1, 3, 5, and 7-10 are rejected under 35 U.S.C. 103 as being unpatentable over Cheng3 in view of Mahieux as applied above, and further in view of Q98621 (UniProt accession Q98621_9DELA (1997)).
Regarding claim 5, the combination of Cheng3 and Mahieux does not teach wherein the Tax protein comprises SEQ ID NO: 3.
However Q98621 teaches a primate T-lymphotropic virus type 3 Tax protein consisting of SEQ ID NO: 3, as shown below, from the first STLV-3 strain ever isolated (STLV-L).
Q98621_9DELA
ID Q98621_9DELA Unreviewed; 350 AA.
AC Q98621;
DT 01-FEB-1997, integrated into UniProtKB/TrEMBL.
DT 01-FEB-1997, sequence version 1.
DE SubName: Full=Tax protein {ECO:0000313|EMBL:CAA61322.1};
GN Name=tax {ECO:0000313|EMBL:CAA61322.1};
OS Simian T-lymphotropic virus 3.
OC Viruses; Riboviria; Pararnavirae; Artverviricota; Revtraviricetes;
OC Ortervirales; Retroviridae; Orthoretrovirinae; Deltaretrovirus.
OX NCBI_TaxID=39101 {ECO:0000313|EMBL:CAA61322.1};
RN [1] {ECO:0000313|EMBL:CAA61322.1}
SQ SEQUENCE 350 AA; 39162 MW; BDD6EAB4A88FA418 CRC64;
Query Match 100.0%; Score 1911; Length 350;
Best Local Similarity 100.0%;
Matches 350; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MAHFPGFGQSLLYGYPVYVFGDCVQADWCPISGGLCSARLHRHALLATCPEHQITWDPID 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MAHFPGFGQSLLYGYPVYVFGDCVQADWCPISGGLCSARLHRHALLATCPEHQITWDPID 60
Qy 61 GRVVSSALQYLIPRLPSFPTQRTTRTLKVLTPPTTATTPKVPPSFFHAVRKHTPFRNNCL 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 GRVVSSALQYLIPRLPSFPTQRTTRTLKVLTPPTTATTPKVPPSFFHAVRKHTPFRNNCL 120
Qy 121 ELTLGEQLPAMSFPDPGLRPQNVYTMWGSSVVCLYLYQLSPPMTWPLIPHVIFCHPEQLG 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 ELTLGEQLPAMSFPDPGLRPQNVYTMWGSSVVCLYLYQLSPPMTWPLIPHVIFCHPEQLG 180
Qy 181 AFLTRVPTKRLEELLYKIFLSTGAILILPENCFPTTLFQPTRAPAIQAPWHTGLLPCQKE 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 AFLTRVPTKRLEELLYKIFLSTGAILILPENCFPTTLFQPTRAPAIQAPWHTGLLPCQKE 240
Qy 241 ITTPGLVWTFTDGSPMISGPCPKEGQPSLVVQSSTFIFQQFQTKANHPAFLLSHKLIHYS 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 ITTPGLVWTFTDGSPMISGPCPKEGQPSLVVQSSTFIFQQFQTKANHPAFLLSHKLIHYS 300
Qy 301 SFHSLHLLFEEYTTVPFSLLFNEKGANVNDDEPQDEPQPPTRGQIAESSV 350
||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 SFHSLHLLFEEYTTVPFSLLFNEKGANVNDDEPQDEPQPPTRGQIAESSV 350
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to perform a method of Cheng3 as modified by Mahieux to investigate interspecies Tax protein functional conservation to select any STLV-3 Tax protein known in the art, including the STLV-3 Tax protein taught by Q98621. One of ordinary skill in the art would be motivated to choose factors from the foundational STLV-3 strain (STLV-L), which is the best studied.
Furthermore, Cheng3 teaching using HTLV-3 Tax protein variants/fragments at least 80% identical to SEQ ID NO: 5 (pg. 26, last para.; pg. 25, para. 4) and as shown below the Tax protein taught by Q98621 is encompassed within at least 95% identity of SEQ ID NO: 5 taught by Cheng3, meaning this STLV-3 Tax protein is considered by Cheng3 to specifically be an HTLV-3 Tax variant encompassed by its disclosure.
95.4% identity in 350 residues overlap; Score: 1852.0; Gap frequency: 0.0%
Q98621 1 MAHFPGFGQSLLYGYPVYVFGDCVQADWCPISGGLCSARLHRHALLATCPEHQITWDPID
Sequence5 1 MAHFPGFGQSLLYGYPVYVFGDCVQADWCPISGGLCSARLHRHALLATCPEHQITWDPID
************************************************************
Q98621 61 GRVVSSALQYLIPRLPSFPTQRTTRTLKVLTPPTTATTPKVPPSFFHAVRKHTPFRNNCL
Sequence5 61 GRVVSSALQYLIPRLPSFPTQRTTRTLKVLTPPTTAATPKIPPSFFHAVKKHTPFRNNCL
************************************ *** ******** **********
Q98621 121 ELTLGEQLPAMSFPDPGLRPQNVYTMWGSSVVCLYLYQLSPPMTWPLIPHVIFCHPEQLG
Sequence5 121 ELTLGEQLPAMSFPDPGLRPQNIYTMWGSSVVCLYLYQLSPPMTWPLIPHVIFCHPEQLG
********************** *************************************
Q98621 181 AFLTRVPTKRLEELLYKIFLSTGAILILPENCFPTTLFQPTRAPAIQAPWHTGLLPCQKE
Sequence5 181 AFLTRVPTKRLEELLYKIFLSTGAIIILPENCFPTTLFQPTRAPAVQAPWHTGLLPCQKE
************************* ******************* **************
Q98621 241 ITTPGLVWTFTDGSPMISGPCPKEGQPSLVVQSSTFIFQQFQTKANHPAFLLSHKLIHYS
Sequence5 241 IATPGLIWTFTDGSPMISGPCPKEGQPSLVVQSSTFIFQQFQTKASHPAFLLSHKLIHYS
* **** ************************************** **************
Q98621 301 SFHSLHLLFEEYTTVPFSLLFNEKGANVNDDEPQDEPQPPTRGQIAESSV
Sequence5 301 SFHSLHLLFEEYTTIPFSLLFNEKGANVDDDEPRDGSQPPARGQIAESPV
************** ************* **** * *** ******* *
Thus, the claimed invention as a whole is prima facie obvious to one of ordinary skill in the art before the effective time of filing in the absence of evidence to the contrary.
Response to Arguments
Although the arguments of 3/30/26 regarding the previous obviousness rejections and current claim amendments (pg. 8-15) were found to be persuasive, new obviousness rejections are presented above.
Conclusion
No claim is allowed.
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/ERIC J ROGERS/Examiner, Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638
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