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 1-22 are currently pending in this application.
Election/Restrictions
Applicant’s election without traverse of Group IV, claims 17-22, in the reply filed 8/8/25 is acknowledged. Claims 1-16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected subject matter, there being no allowable generic or linking claim. Claims 17-22 have been considered on the merits, and all arguments have been fully considered.
Previous Rejections
Status of the rejections: the previous claim rejections under 35 USC §§ 102 and 103 and nonstatutory double patenting are withdrawn in view of the 1.130 Decl. of Nakauchi filed 12/9/25.
Claim Interpretation
Claim 17 is interpreted as being implicitly limited to autologous adoptive cellular therapies as indicated by the current claim language.
The term “immune cell” is interpreted as encompassing mast cells, Kupffer cells, microglia, and Langerhans cells (see e.g., instant [0063]).
Under a broadest reasonable interpretation, the term “medium” in claim 17 is interpreted as being limited to an aqueous composition compatible with immune cell culture (e.g., comprising a buffer and inorganic salts), such as an aqueous solution or hydrogel (see e.g., instant [0062]; [0037]).
Under a broadest reasonable interpretation, the term “polyvinyl alcohol” (or PVA) is interpreted as encompassing any polymer of vinyl alcohol, e.g., [CH2CH(OH)]n wherein n is any positive integer, including crosslinked PVA, as this term is commonly used in the art.
In claim 17, the term “expanding” is interpreted as requiring at least a subset of the immune cells to perform at least one cell division thereby increasing the total number of immune cells regardless of whether the cells of the subset are considered “of interest.” While it is improper to read a specific order of steps into method claims, as a matter of logic/grammar step a) must precede step b) and step c) must precede step d). However the order of steps a) and c) is not limited, meaning expansion of the immune cells may be performed on un-isolated immune cells in the recited medium.
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 17-22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, and 35 U.S.C. 112(b) as failing to comply with the written description requirement. 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 claims are directed to methods comprising administering a therapeutically effective amount of immune cells to subject for an autologous adoptive cellular therapy wherein the immune cells are prepared by expanding in a serum albumin-free cell culture medium comprising polyvinyl alcohol.
The claims are broad in that terms “subject”, “immune cells”, “administering” and “the expanded immune cells” composition are only limited by the knowledge of the skilled artisan in view of the prior art. Furthermore, the claims are broad in that the term “therapeutically effective amount” is a variable that depends on multiple parameters in the claim, including the broad parameters of (1) type of subject (e.g., disease and severity, age, weight), (2) type of immune cells, (3) route of administering, and (4) formulation of the expanded immune cells being administering.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described. In the instant case, the specification fails to provide a single working example, and thus no exemplary species of subject, immune cell, administering or formulation is disclosed. Instead the specification describes prophetic methods with representative species at a high level of generality based on mouse or human T cells expanded in medium comprising polyvinyl alcohol (e.g., transformed leukemic cells or engineered CAR-T cells) (Example 1; FIG. 1-2).
The genus of subject encompasses any subject in need of an adoptive cellular therapy with immune cells, including humans, animals, insects and mollusks, with no restriction on subject selection, e.g., to only those having an adaptive immune system or to any constrained disease or disorder, e.g., to autoimmune disorders. The genus of immune cells encompasses any type of immune cell, including mast cells, Kupffer cells, microglia, and Langerhans cells. The only type of immune cells used in the working examples are T lymphocytes expressing a CAR transgene (Example 1). The genus of administering encompasses any route, such as enteral, parenteral, and topical. The genus of compositions comprising the expanded immune cells being administering encompasses any excipient or carrier (see [0013], [0047]) or nothing at all besides the immune cells.
While the art teaches various adoptive cell therapies in various mammalian subjects using various types of immune cells (e.g., T cells, NK cells, macrophage or dendritic cells) formulated in an isotonic buffered aqueous solution administered by injection and/or intravenously often specifically for treating cancer or an infectious disease (see e.g., Han et al., Cell Transplant 33 (2024) at Fig. 2), the prior art does not teach the full scope for these 4 parameters of the claim 17.
As claim 17 requires an “therapeutically effective amount” of the expanded immune cells be administered to the subject, this asserts an effective amount exists over the full scope of the claim, e.g., regarding the subject genus, the immune cell genus, unlimited routes of administration and unlimited formulation. The instant application is silent as to any effective amount to administer to a subject. Thus, the written description lacks a representative number of species for the functional genus of an effective amount and methods of administering such.
The skilled artisan could not rely upon the disclosure in the specification such that the specification would sufficiently describe that Applicant was in possession of the full scope of the claimed methods encompassed by the broad terms of “subject”, “immune cells”, and administering without limits. The dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim for all parameters.
Furthermore, the term “effective amount” has been held to be indefinite when the claim fails to state the function which is to be achieved and more than one effect can be implied from the specification or the relevant art. In re Fredericksen, 213 F.2d 547, 102 USPQ 35 (CCPA 1954). MPEP 2173.05(c). Thus, claims 17-22 are indefinite by reference to a “therapeutically effective amount” which is a variable (MPEP §2173.05(b)) depending on the broad 4 parameters discussed above. The dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim.
The skilled artisan could not rely upon the disclosure in the specification such that the specification would sufficiently describe that Applicant was in possession of the breadth of subjects (e.g., having any disease or disorder), breadth of immune cells (e.g., mast cells, Langerhans cells or T-helper cells), and all the routes of administration (e.g., topical) and formulations (oral tablet) as encompassed by the claims to effectuate a therapy and provide a therapeutically effective amount as required by the claim limitations at the earliest effective filing date. Instead, a small set of representative species are described along with an invitation to the skilled artisan to adapt these to the broad scopes of each genus term without a clear nexus between the disclosed species and the full claim scope.
35 USC § 112(a), Scope of Enablement
Claims 17-22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification does not enable any person, skilled in the art to which it pertains or with which it is most nearly connected to, to provide an adoptive cellular therapy with an effective amount of expanded immune cells over the full scope of the claims. The application is enabled wherein the subject is mammalian and is in need of adoptive immune cellular therapy to treat a cancer, the immune cells are T cells or dendritic cells, and the administering is via injection and/or intravenously in a pharmaceutical composition formulated for such.
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.
As noted in the written description rejection, the claims are broad in that terms “subject”, “immune cells”, “administering” and “the expanded immune cells” composition are only limited by the knowledge of the skilled artisan in view of the prior art. Furthermore, the claims are broad in that the term “therapeutically effective amount” is a variable that depends on multiple parameters in the claim, including the broad parameters of (1) type of subject (e.g., disease and severity, age, weight), (2) type of immune cells, (3) route of administering, and (4) formulation of the expanded immune cells being administering.
As noted in the previous section, the prior art does not teach the full scope of adoptive cellular therapies encompassed by the claims regardless of the polyvinyl alcohol expansion step. Thus, these aspects of scope must be shown to a reasonable extent 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 artisan.
The amount of direction and guidance as well as any working examples provided:
The instant specification provides no working example of administering any immune cell to a subject. Rather, the only example is a method of in vitro expanding T cells to prepare them for such uses. Thus, there is no evidence in the instant application or the prior art that the scope of subjects, diseases, types of immune cells, administration routes and/or formulations encompassed by the claims could predictably result in either an effective amount or adoptive cellular therapy across the entire scope of the claims. Undue experimentation would be required to fill these gaps and unpredictability. Undue experimentation is required to fill these gaps in the prior art with the breadth of the claims. Given the extreme breath of the claims, lack of any working example, the limited guidance provided in the specification, the lack of guidance in the prior art for such broad scope; undue and/or unreasonable experimentation would have been required for one skilled in the art to produce the recited product over the full scope of the methods of any of claims 17-22.
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.
Claim 17-22 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 pre-AIA the applicant regards as the invention.
Claims 17 recites the term “the immune cells of interest”, which lacks sufficient antecedent basis in the claim. Furthermore, the phrase “of interest” is indefinite for being relative and subjective because neither the claim nor the specification provides a standard or means for determining the requisite level of “interest” to inform the skilled artisan of the metes and bounds of this limitation. Claim 17 is ambiguous as to whether “the immune cells” in step c) are any immune cells generally and/or “the immune cells of interest.” Similarly, claim 19 is also ambiguous as to whether “the immune cells” are referring specifically to “the immune cells of interest” and/or “the immune cells” in claim 17. Claims 18 and 20-22 are included in this rejection for depending on indefinite claim 17 and/or 19.
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 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over Sobol (WO2019183117A1, priority to 2019/03/19) in view of Strehl (Strehl et al., Int J Nanomedicine 10: 3429-45 (2015)).
Sobol teaches methods of administering via intravenous injection to a subject modified dendritic cells (Ad-p53 DC) prepared by culturing in vitro in order to treat cancer ([0036], [00168]; [00176]; [0063]; Examples). Sobol teaches making the dendritic cells by methods comprising obtaining a blood sample from a patient, isolating PBMC from the sample, producing dendritic cells (DC) in cell culture from monocytes in the PBMC, and generating isolated dendritic cells specific to a p53 antigen for autologous adoptive cell therapy back to the patient (FIG. 1; [0033]; Example 2).
Regarding claim 17, Sobol does not teach the step of expanding immune cells in a serum-free cell culture medium comprising polyvinyl alcohol.
However Strehl teaches the addition of the polyvinyl alcohol (PVA-SPION) in media increased the survival in culture of monocytes and their descendants (macrophages) (Fig. 4; pg. 3436, left col., last para., to pg. 3437, left col., 1st para.). Further, Strehl teaches obtaining a blood sample comprising immune cells from a patient, isolating PBMCs and then further isolating monocyte immune cells therefrom, such as for differentiating in culture into monocyte descendants (pg. 3431, right col., 2nd para., to pg. 3432, right col., 1st para.). Strehl teaches methods of incubating these isolated monocytes in a serum-free culture medium (RPMI 1640) comprising polyvinyl alcohol (PVA-SPION) as well as culturing monocytes in a serum-containing medium comprising polyvinyl alcohol for 3-6 days (id.).
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to perform the method of Sobol wherein the monocytes in the PBMCs and their differentiated dendritic cell descendants are cultured in a medium in the presence of polyvinyl alcohol as taught by Strehl. One of ordinary skill in the art would be motivated by Strehl teaching improved immune cell survival in culture due to polyvinyl alcohol (PVA-SPION).
Regarding claim 18, both Sobol and Strehl teach wherein the biological sample comprising PBMC is a blood sample or apheresis product thereof as noted above.
Claims 17-22 are rejected under 35 U.S.C. 103 as being unpatentable over Westoby (US20210163893A1) in view of Abbot (US20160137980A1).
Regarding claim 17, Westoby teaches methods of adoptive cellular therapy comprising administering therapeutically effective amounts of engineered autologous immune cells (e.g., T cells) to a subject to treat cancer, e.g., via intravenous injection and formulated as such ([0107]; [0184]; [0568]; [0932]; [0988]). Westoby teaches wherein the T cells are isolated from a biological sample obtained from a subject ([0067]) and that such T cells can be expanded in vitro for use in treating subjects ([0003]; Table E1; Example 1; FIG. 2-3). Westoby teaches using serum-free media in any step ([0675]; [0077]).
Westoby does not teach wherein the T cells are expanded in a serum albumin-free cell culture medium comprising polyvinyl alcohol.
However Abbot teaches methods of expanding in vitro T cells in a serum-free medium culture comprising polyvinyl alcohol (PVA-microsphere having an immobilized T-cell stimulatory ligand, such as anti-CD3) ([0004]; [0018]; [0038]-[0040]; [0057]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to perform an autologous adoptive cell therapy method of Westoby using T cells to treat a cancer/tumor wherein the T cells are expanding in vitro in a serum-free medium comprising polyvinyl alcohol as taught by Abbot. One of ordinary skill in the art would be motivated by Abbot teaching including the ligand-PVA microspheres both induces expansion and T cell activation ([0056]).
Regarding claim 18, Westoby teaches obtaining immune cells from a blood sample ([0067]; [0198]; [0203]).
Regarding claims 19-20, Westoby teaches using immune cells that are T cells (lymphocytes) ([0197]; claim 1).
Regarding claims 21-22, Westoby teaches wherein the T cells are genetically engineered to express a CAR that binds a cancer epitope for use in adoptive cell cancer therapies ([0170], [0184]; [0075]-[0076]). Therefore the claimed invention as a whole is prima facie obvious before the effective filing date in the absence of evidence to the contrary.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIC J ROGERS whose telephone number is (571)272-8338. The examiner can normally be reached Monday - Friday 9:00-6:00.
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/ERIC J ROGERS/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638