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
Applicant’s amendments and remarks, filed 10/29/2025, are acknowledged.
Claims 2-4, 7-14, 16-30, and 33-72 are canceled.
Claims 1 and 5 are amended.
Claim 73 is new.
Claims 1, 5-6, 15, 31-32, and 73 are pending.
Claims 31 and 32 are withdrawn from consideration due to the restriction requirement mailed 11/02/2022.
It is noted that Applicant did not underline the language “comprising the CAR” in claim 1, although this language was not previously presented. 37 CFR 1.121(c) states that: “Amendments to a claim must be made by rewriting the entire claim with all changes (e.g., additions and deletions) as indicated in this subsection, except when the claim is being canceled. Each amendment document that includes a change to an existing claim, cancellation of an existing claim or addition of a new claim, must include a complete listing of all claims ever presented, including the text of all pending and withdrawn claims, in the application. The claim listing, including the text of the claims, in the amendment document will serve to replace all prior versions of the claims, in the application. In the claim listing, the status of every claim must be indicated after its claim number by using one of the following identifiers in a parenthetical expression: (Original), (Currently amended), (Canceled), (Withdrawn), (Previously presented), (New), and (Not entered).” For the interest of compact prosecution and customer service, Examiner has considered Applicant’s remarks and amendments filed 10/29/2025. Applicant is advised that failure to ensure claims are compliant in any future reply will be considered non-compliant and will result in a Notice of Non-Compliant Amendment.
As such, claims 1, 5-6, 15, and 73 are pending examination and currently under consideration for patentability under 37 CFR 1.104.
DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 10/29/2025 has been entered.
Withdrawn Rejections
Applicant’s arguments, see page 4, filed 10/29/2025, with respect to claim 72 rejected under 35 USC 112(b) as allegedly being indefinite have been fully considered and are persuasive. The issue regarding the claims comprising indefinite language have been sufficiently addressed through amendments to the claims. Specifically, Examiner acknowledges that claim 72 is canceled thus rendering the rejection moot. As such, the rejection under 35 USC 112(b) is withdrawn.
Applicant’s arguments, see pages 4 and 5, filed 10/29/2025, with respect to claims 1, 5-7, 15, and 71-72 rejected under 35 USC 112(a) as allegedly introducing new matter have been fully considered and are persuasive. The issue regarding the specification failing to disclose that the CAR-T cells are generated from the CD34- fraction of the mobilized peripheral blood have been sufficiently addressed. Specifically, Examiner acknowledges the section of the specification that Applicant highlighted in their response, which teaches the “CD34+ cells were diverted to a specific research project, while the CD34- fraction was rested overnight at 4°C… Prior to cryopreservation in liquid nitrogen, CD4/8 enrichment was performed using CD4 and CD8 magnetic microbeads to deplete myeloid cells by positive selection of T-cells… CAR T-cells using both ss [steady state] and mob [enriched CD4/8 T-cells after G-CSF mobilization] starting cells were manufactured in parallel…”. Further, Examiner acknowledges that claims 71 and 72 are canceled thus rendering the rejection moot. As such, the new matter rejection under 35 USC 112(a) is withdrawn.
The rejection of claims 1, 5-7, 15, and 71-72 under 35 USC 112(a) as allegedly lacking written description is modified in favor of the new limitations added in the amendment filed 10/29/2025. Specifically, Examiner acknowledges that claim 1 was amended to limit the collection of mobilized peripheral blood to 5 days after the subcutaneous administration of the agent, and claim 5 was amended to recite the limitation “wherein the antigen binding domain comprises means for specifically binding to CD33”. Further, Examiner acknowledges that claims 71 and 72 are canceled thus rendering the rejection moot. Applicant’s arguments, see pages 5-9, filed 10/29/2025, with respect to claims 1, 5-7, 15, and 71-72 rejected under 35 USC 112(a) have been fully considered.
Applicant’s remarks, see pages 9-12, filed on 10/29/2025, with respect to claims 1, 5-7, 15, and 71-72 rejected under 35 USC 103 as allegedly being unpatentable over Kunkele et al, Gurman et al, Ripa et al, and Kenderian et al have been fully considered and are persuasive. Examiner acknowledges that claims 7, 71, and 72 are canceled, thus rendering the rejection moot. Further, Examiner acknowledges that claims 1 and 5 were amended to recite to limit the collection of mobilized peripheral blood to 5 days after the subcutaneous administration of the agent, and claim 5 was amended to recite the limitation “wherein the antigen binding domain comprises means for specifically binding to CD33. Additionally, Examiner acknowledges that the claims recite making a CAR T cell or protein comprising introducing a nucleic acid comprising a sequence encoding the CAR into a T cell obtained from a CD34 negative cell fraction of the mobilized peripheral blood of the subject which is not disclosed by the cited art. As such, the rejection of claims 1, 5-7, 15, and 71-72 under 35 USC 103 is withdrawn.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.821 - 1.825 because it does not contain a "Sequence Listing" as a separate part of the disclosure or a CRF of the “Sequence Listing.”.
Required response - Applicant must provide:
A "Sequence Listing" part of the disclosure; together with
An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(a)(2);
A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.821(a)(4); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(a)(3).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
If the "Sequence Listing" part of the disclosure is submitted according to item 1) c) or d) above, applicant must also provide:
A CRF in accordance with 37 CFR 1.821(e)(1) or 1.821(e)(2) as required by 1.825(a)(5); and
A statement according to item 2) a) or b) above.
Specific deficiency - This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825.
The sequence disclosures are located on page 58 of the specification filed 05/21/2025.
Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter;
If the "Sequence Listing" part of the disclosure is submitted according to item 1) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see page 62). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claim 1 is objected to because of the following informalities:
Claim 1, line 8: “thereby the making CAR T cell” should read “thereby a CAR T cell”.
Appropriate correction is required.
Claim Interpretation
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
This application includes one claim limitation that use the word “means” or “step” and is being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph because the claim limitation(s) recite(s) sufficient structure, materials, or acts to entirely perform the recited function. Such claim limitation is: “means for specifically binding to CD33” in claim 5.
Because this claim limitation is being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, it is being interpreted to encompass only the corresponding structure, material, or acts described in the specification as performing the claimed function, and equivalents thereof. Specifically, this claim limitation is being interpreted to encompass gemtuzumab, an anti-CD33 monoclonal antibody, as described in the specification (see Example 2; page 56, lines 6-13).
If applicant does not intend to have this limitation interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, applicant may: (1) amend the claim limitation to avoid it being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph (e.g., by reciting sufficient structure to perform the claimed function); or (2) present a sufficient showing that the claim limitation recites sufficient structure to perform the claimed function so as to avoid it being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph.
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, 15, and 73 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. 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 MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Claim 1 is drawn to a method for making a T cell comprising a chimeric antigen receptor (CAR) from mobilized peripheral blood, the method comprising subcutaneously administering to a subject an agent that induces migration of hematopoietic stem cells from the subject's bone marrow to the subject's peripheral blood to generate the mobilized peripheral blood; and introducing a nucleic acid comprising a sequence encoding the CAR into a T cell obtained from a CD34 negative cell fraction of the mobilized peripheral blood of the subject, thereby making the CAR T cell, wherein the mobilized peripheral blood is collected via apheresis from the subject 5 days after the subcutaneous administration of the agent, wherein the agent is granulocyte colony stimulating factor (G-CSF).
Claim 15 is drawn to the method of claim 1, further comprising obtaining the hematopoietic stem cells from the same mobilized peripheral blood sample obtained from the subject via the same apheresis.
Claim 73 is drawn to a method for making a genetically engineered T cell from mobilized peripheral blood, the method comprising subcutaneously administering to a subject an agent that induces migration of hematopoietic stem cells from the subject's bone marrow to the subject's peripheral blood to generate the mobilized peripheral blood; and introducing a nucleic acid comprising a sequence encoding a protein into a T cell obtained from a CD34 negative cell fraction of the mobilized peripheral blood of the subject, thereby making the genetically engineered T cell comprising the protein, wherein the mobilized peripheral blood is collected via apheresis from the subject 5 days after the subcutaneous administration of the agent, wherein the agent is granulocyte colony stimulating factor (G-CSF).
The specification discloses of generating CAR T cells from G-CSF mobilized PBMC (see Example 1). The attributes of T cells obtained from steady-state compared with G-CSF mobilized blood were evaluated; PBMC from normal volunteers before and after administration of 4-5 days of G-CSF (see pg. 54, lines 15-18). Three (3) to five (5) L of apheresed PBMC was collected after G-CSF injection (see pg. 54, lines 18-19). In this study, the null hypothesis was that G-CSF primed T cells (CARTmob) would proliferate less well ex vivo and would mediate a poorer anti-tumor effect than CART cells made from steady-state unmobilized T cells from the same donor (CARTSS) (see Example 1). If the null hypothesis was rejected (that is, the anti-tumor the function of CARTmob = antitumor function of CARTSS) this would open the way to using a single G-CSF mobilized apheresis as the source for both stem cells and T cells for clinical studies that either (1) rely on allogeneic T cells for patients who have or will undergo a
standard-of-care allogeneic stem cell transplant, or (2) are designed as a tandem gene-edited
stem cell transplant plus CART cell administration protocol (see Example 1). The in vitro studies revealed a broadly similar anti-tumor effect when CARTmob were compared to CARTSS (see pg. 55, lines 1-3). Surprisingly, in vivo xenograft studies showed that the anti-tumor effect and proliferation of CARTmob may be superior to those of CARTSS (see FIGs. 1A-1C), without evidence of increased toxicity to the xenografted mice. Further studies are being pursued to verify these results and to explain the mechanism for the differential efficacy (see pg. 55, lines 5-6).
Additionally, the specification discloses of CAR T-cell manufacture and analysis of ssCAR33 and mobCAR33 infusion product (see Example 2). Healthy volunteer donors underwent a blood draw of 30 mL of whole blood anti-coagulated in EDTA (see pg. 55, lines 14-15). PBMCs were isolated by Ficoll gradient separation and cryopreserved (see pg. 55, lines 15-18). After 5 days of subcutaneous G-CSF therapy, the donor underwent a single apheresis and the mobilized apheresis product was collected in accordance with standard clinical procedures (see pg. 55, lines 18-20). The apheresis product was resuspended in autologous plasma and transported fresh; CD34+ cells were diverted and the CD34- fraction was rested overnight (see pg. 55, lines 21-27). The specification discloses that a CAR33 was used, wherein the CAR33 construct used is a 2nd generation CAR with a 41BB co-stimulatory domain and an scFv that is based on the anti-CD33 monoclonal antibody gemtuzumab (see pg. 56, lines 6-12). T-cell expansions were performed on PBMC that were collected at steady state (ss), or enriched CD4/8 T-cells after G-CSF mobilization (mob) cells (see pg. 57, lines 1-3).
However, the specification fails to disclose that Applicant was in possession of the claimed method. Specifically, the specification fails to disclose the structure (i.e., nucleic acid sequence) of the large genus of CARs. Lastly, the specification fails to disclose that Applicant was in possession of a method of making a genetically engineered T cell comprising introducing a nucleic acid comprising a sequence encoding any protein into a T cell as described in claim 73.
Although the specification discloses CAR33 T cells developed from G-CSF mobilized PBMCs comprising a 41BB co-stimulatory domain and a scFv based on the anti-CD33 monoclonal antibody gemtuzumab (see Example 2; page 56, lines 6-13), the claims are not limited to this CAR, and are inclusive of any CAR that targets any tumor antigen comprising any intracellular signaling domain and any transmembrane domain. This indicates that there are hundreds, if not thousands, of possible CAR T cells encompassed by the claims. Thus, the claims encompass a vast genus of CAR T cells that have the claimed functions. However, the specification provides limited guidance on the structure and steps required for maintaining the claimed function(s). Therefore, the specification does not provide adequate written description to identify the broad and variable genus of CAR T cells because, inter alia, the specification does not disclose a correlation between the necessary structure of the CAR, and the function(s) recited in the claims; and thus, the specification does not distinguish the claimed genus from others, except by function. Further, the specification fails to provide method steps that result in generating a large genera of CAR T cells. Although the term CAR does impart some structure, the structure that is common to CARs is generally unrelated to its specific binding function; therefore, correlation is less likely for CARs than for other molecules. Accordingly, the specification does not define any structural features commonly possessed by the members of the genus, because while the description of an ability of the claimed substance may generically describe the molecule’s function, it does not describe the substance itself. A definition by function does not suffice to define the genus because it is only an indication of what the substance does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves the result. In addition, because the genus of substances is highly variable (i.e. each substance would necessarily have a unique structure, See MPEP 2434), the generic description of the substance is insufficient to describe the genus. Further, given the highly diverse nature of CARs, particularly in antigen binding domains, even one of skill in the art cannot envision the structure of a CAR by only knowing its binding characteristics. Thus, the specification does not provide substantive evidence for possession of this large and variable genus, encompassing a potentially massive number of CARs and variants thereof claimed only be a functional characteristic(s) and/or partial structure.
A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not sufficient identifying characteristics for written description purposes, even when accompanied by a method of obtaining the agent. The specification does not adequately describe the correlation between the chemical structure and function of the genus, such as structural domains or motifs that are essential and distinguish members of the genus from those excluded. Thus, the genus of CARs has no correlation between their structure and function.
MPEP § 2163.03(V) states:
While there is a presumption that an adequate written description of the claimed invention is present in the specification as filed, In re Wertheim, 541 F.2d 257, 262, 191 USPQ 90, 96 (CCPA 1976), a question as to whether a specification provides an adequate written description may arise in the context of an original claim. An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. "Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement. “Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
Applicant has not shown possession of a representative number of species of CARs. The disclosure of only one or two species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.") (MPEP 2163).
The instant claims do not fully describe the structure of the CAR to achieve the required function. Accordingly, the specification also does not provide adequate written description to identify the broad genus of CARs, claimed only by a function characteristic(s) and not structures per se, because inter alia, it does not describe a sufficient number and/or a sufficient variety of representative species to reflect the breadth and variation within the claimed genus. Consequently, based on the lack of information within the specification, there is evidence that a representative number and a representative variety of the numerous CARs had not yet been identified and thus, the specification represents little more than a wish for possession. Therefore, one of skill in the art would not conclude that Applicant was in possession of the broad and highly variable genus of CARs claimed only by a partial structure and functional characteristic(s). Thus, the CARs described by the instant claims encompasses an overly broad genus and the functional outcome.
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), it is noted that to show invention, a patentee must convey in its disclosure that is “had possession of the claimed subject matter as of the filing date. Demonstrating possession “requires a precise definition” of the invention. To provide this precise definition” for a claim to a genus, a patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen at page 1358). Also, it is not enough for the specification to show how to make and use the invention, i.e., to enable it (see Amgen at page 1361). An adequate written description must contain enough information about the actual makeup of the claimed products — “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361). Most significant to the present case, the Court held that "knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies" (Amgen at 1361). The idea that written description of an antibody can be satisfied by the disclosure of a newly-characterized antigen “flouts basic legal principles of the written description requirement” as it “allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen... And Congress has not created a special written description requirement for antibodies” (Amgen at page 1362).
Abbvie v. Centocor (Fed. Cir. 2014) is also relevant to the instant claims. In Abbvie, the Court held that a disclosure of many different antibodies was not enough to support the genus of all neutralizing antibodies because the disclosed antibodies were very closely related to each other in structure and were not representative of the full diversity of the genus. The Court further noted that functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support especially in technology fields that are highly unpredictable where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus.
The instant case has many similarities to AbbVie above. First, the claims clearly attempt to define the genus of CARs by the function of comprising an antigen binding domain comprising a means for specifically binding to CD33 (i.e., gemtuzumab), an intracellular signaling domain, and a transmembrane domain. As noted by AbbVie above, functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description. Second, there is no information in the specification based upon which one of skill in the art would conclude that the disclosed species for which applicant has identified as having the recited functions would be representative of the entire genus. The specification discloses no structure to correlate with the function. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim.
CAR T cell therapy is unpredictable, and recent studies demonstrate that many aspects of CAR signaling are unique, distinct from endogenous TCR signaling, and potentially even distinct among various CAR constructs (see e.g. Lindner et al. (Sci Adv. 2020 May 20;6(21):eaaz3223); previously submitted with the Office action mailed 11/21/2024). Thus, rigorous and comprehensive proteomic investigations are required for rational engineering of improved CARs (see e.g. abstract). CAR T cell therapy has transformed many aspects of clinical and translational oncology, and the successes achieved to date have led to a rapid expansion of clinical and basic science research efforts in this area (see e.g. page 6, left column, second paragraph). However, this explosion has, in many ways, outpaced fundamental investigations into how these receptors work, which threatens to limit our ability to improve upon current designs in an optimal fashion (see e.g. page 6, left column, second paragraph). Characteristics such as CAR avidity, scFv affinity, antigen-binding domain structure and size, hinge/spacer region length and design, and transmembrane domain choice all affect the kinetics and dynamics of signaling pathway activation, just as choice of cytoplasmic signaling moieties affects the specific pathways that are proximally activated (see e.g. page 6, left column, fourth paragraph).
CAR-T cell therapies have been approved by the FDA to treat some kinds of leukemias and lymphomas, as well as multiple myeloma (see page 13, American Cancer Society “CAR T-cell therapy and its side effects”, downloaded from https://www.cancer.org/cancer/managing-cancer/treatment-types/immunotherapy/car-t-cell1.html on 11/13/24; last revised December 20, 2023); previously submitted with the Office action mailed 11/21/2024). At least six different therapies have been approved for use by the US Food and Drug Administration (FDA) in these cancers (see p. 13, American Cancer Society, and entire reference section).
According to Guzman et al (Current Oncology Reports (2023) 25:479–489); previously submitted with the Office action mailed 11/21/2024), CAR-T therapy has shown success in treating hematological malignancies (see e.g. page 480, left column, second paragraph). Despite revolutionary progress in blood cancers, equivalent success has yet to be duplicated in solid tumor malignancies (see e.g. page 480, left column, second paragraph). Significant developments such as allogeneic or “of-the-shelf” CAR-T cells, which involve T cells from a donor's circulating blood, have attempted to improve success. However, solid tumors present unique challenges, such as a hostile tumor microenvironment (TME) and heterogeneous antigen expression that hinder similar advancements (see e.g. page 480, left column, second paragraph). A central difference between solid tumors and hematological cancers is the intricacy in detecting a perfect target antigen (see e.g. page 480, left column, third paragraph). While target heterogeneity exists in blood cancers, these disorders more commonly tend to express individual markers (i.e., B-cell marker CD19) (see e.g. page 480, left column, third paragraph). Additionally, solid tumors more often have tumor-associated antigens (TAA), where this antigen is highly expressed on the tumor itself but also at low levels in normal tissues. Furthermore, solid tumors display TAA heterogeneity between tumor types (primary vs. metastatic) and patients with the same cancer (see e.g. page 480, left column, third paragraph) Consequently, a significant roadblock is designing a proper CAR-T cell with the capability of finding an ideal target antigen in solid tumors (see e.g. page 481, right column, second paragraph to page 482, left column, first paragraph). Once a CAR-T cell invades the endothelial barrier, it must continue to survive and persist in the inhospitable tumor microenvironment (TME) (see e.g. page 481, right column, second paragraph to page 482, left column, first paragraph). The TME presents a myriad of obstacles to CAR-T therapy, including the tumor stroma composed of suppressive cell types such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) and hypoxic conditions that hamper its execution (see e.g. page 481, right column, second paragraph to page 482, left column, first paragraph). Further, on-target off-tumor toxicity can be detrimental when CAR-T cells are directed to attack a tumor antigen that is also present in normal tissues (see e.g. page 482, left column, fourth paragraph). These data suggest that treatment of solid tumors or prevention of cancer with CAR-T cell therapy would be highly unpredictable.
Furthermore, regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to that subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods. Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920-23, 69 USPQ2d 1886, 1890-93 (Fed. Cir. 2004).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
For example, Kunkele et al (Cancer Immunol Res; 3(4) April 2015); previously submitted with the Office action mailed 11/21/2024) disclose of constructing CD171-specific CARs using (G4S)3 peptide-linked VL and VH segments of the CE7-IgG2 monoclonal antibody; the scFv was codon optimized and subsequently linked to variable spacer length domains based on 12AA [short spacer (SS)/”hinge only”], 119AA [medium spacer (MS)/”hinge-CH3”] or 229AA [long spacer (LS)/”hinge-CH2-CH3”] derived from human IgG4-Fc (see pg. 369, left col). All spacers were linked to the transmembrane domain of human CD28 and to signaling modules comprising either the cytoplasmic domain (i) of 4-1BB alone (2G CAR) or (ii) of CD28 (mutant) and 4-1BB (3G CAR), with each signaling module fused to the human CD3-ζ endodomain (see pg. 369, left col). The cDNA clones encoding CAR variants were linked to a downstream T2A ribosomal skip element and truncated EGF receptor (EGFRt), cloned into the epHIV7 lentiviral vector, and CD171-CAR lentiviruses were produced in 293T cells (see pg. 369, left col). Further, Kunkele et al disclose that samples of heparinized blood were obtained from healthy donors and PBMCs were isolated using ficoll, and CD8+CD45RO+CD62L+ central memory T cells were isolated using immunomagnetic microbeads (see pg. 369, left col). CD171-CAR and mock control T cells were expanded using a rapid expansion protocol (see pg. 369, right col).
Additionally, Kunkele et al. (Biol Blood Marrow Transplant 25 (2019) 223-232; submitted in previous Office Action mailed 07/05/2023) teach of developing CD171-specific CAR T cells comprising the cytoplasmic domain of either 4-1BB alone (2nd generation CAR) or CD28 (mutant) and 4-1BB (3rd generation CAR) (see pg. 224, left col.). The cDNA clones encoding CAR variants were linked to a downstream T2A ribosomal skip element and truncated EGF receptor (EGFRt) and then cloned into the epHIV7 lentiviral vector (see pg. 224, left col.). Frozen apheresis products from the patients with neuroblastomas were thawed in Normosol R plus 10% human albumin (see pg. 224, col. 1). Peripheral blood mononuclear cells (PBMCs) were isolated by standard protocol using Ficoll-Paque density gradient medium either from a thawed patient apheresis product or from a fresh collected HD apheresis product (see pg. 224, col. 1). Kunkele et al. teach that transduction was performed 1 day after activation by centrifugation at 800 x g for 30 minutes at 32°C with lentiviral supernatant supplemented with 1 mg/mL protamine sulfate (see pg. 224). Further expansion of CAR-T cells was carried out by coculture with irradiated PBMCs and Epstein-Barr virus-transformed lymphoblastoid cell lines with OKT3 (30 ng/mL) in Gibco RPMI medium (see pg. 224, right col.).
Lastly, Battram et al (Molecular Therapy: Methods & Clinical Development Vol. 26 September 2022, pages 207-223); previously submitted with the Office action mailed 11/21/2024) disclose of T cells isolated from G-CSF-treated multiple myeloma (MM) patients are suitable for the generation of BCMA-directed CAR-T cells (see Title). Battram et al teach that autologous cell immunotherapy using B cell maturation antigen (BCMA)-targeted CAR-T cells is an effective novel treatment for MM; this therapy has only been used for relapsed and refractory patients, at which stage the endogenous T cells used to produce the CAR-T cells are affected by the immunosuppressive nature of advanced MM and/or side effects of previous therapies (see Abstract). An alternative pool of “fitter” T cells is found in leukocytoapheresis products that are routinely collected to obtain hematopoietic progenitor cells for autologous stem cell transplantation (ASCT) early in the treatment of MM (see Abstract). However, to mobilize the progenitor cells (i.e., CD34+ stem cells), patients are dosed with G-CSF which is reported to adversely affect T cell proliferation, function, and differentiation (see Abstract). Battram et al found that G-CSF administered, over a course of 4 days, had a minimal impact on T cell phenotype when added in vitro or administered to patients (see Abstract; Fig. 3A). Moreover, Battram et al found that CAR-T cell fitness and anti-tumor activity were unaffected when generated from G-CSF-exposed T cells; overall, Battram showed that ASCT apheresis products are a suitable source of T cells for anti-BCMA CAR-T cell manufacture (see Abstract).
As such, the art indicates that Applicant has not invented nor demonstrated possession of the various species of CAR-T cells developed by peripheral blood that was mobilized by an agent as claimed in the present invention.
Further, the skilled artisan cannot envision the detailed chemical structure of the encompassed CARs, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: ... To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using “such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
Regarding the encompassed antibodies, the functional characteristics of antibodies (including binding specificity and affinity are dictated on their structure. Amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. For example, Vajdos et al. (J Mol Biol. 2002 Jul 5;320(2):415-28 at 416); previously submitted with the Office action mailed 11/21/2024) teaches that, “ … Even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site." The art shows an unpredictable effect when making single versus multiple changes to any given CDR. For example, Brown et al. (J Immunol. 1996 May;156(9):3285-91 at 3290 and Tables 1 and 2); previously submitted with the Office action mailed 11/21/2024), describes how the VH CDR2 of a particular antibody was generally tolerant of single amino acid changes, however the antibody lost binding upon introduction of two amino changes in the same region.
The claims encompass an extremely large number of possible CARs that have specific required functions. In the instant application, neither the art nor the specification provide a sufficient representative number of CARs or a sufficient structure-function correlation to meet the written description requirements.
Regarding the encompassed proteins and peptides, protein chemistry is one of the most unpredictable areas of biotechnology. This unpredictability prevents prediction of the effects that a given number or location of mutation will have on a protein (such as TNF or a cytokine) as taught by Skolnick et al. (Trends Biotechnol. 2000 Jan;18(1):34-9); previously submitted with the Office action mailed 11/21/2024), sequence-based methods for predicting protein function are inadequate because of the multifunctional nature of proteins (see e.g. abstract). Further, just knowing the structure of the protein is also insufficient for prediction of functional sites (see e.g. abstract). Sequence to function methods cannot specifically identify complexities for proteins, such as gain and loss of function during evolution, or multiple functions possible within a cell (see e.g. page 34, right column). Skolnick advocates determining the structure of the protein, then identifying the functionally important residues since using the chemical structure to identify functional sites is more in line with how a protein actually works (see e.g. page 34, right column).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990); previously submitted with the Office action mailed 11/21/2024) who teach that replacement of a single lysine residue at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al. (Mol. Cell. Biol., 8:1247-1252, 1988); previously submitted with the Office action mailed 11/21/2024) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Further, Miosge (Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):E5189-98); previously submitted with the Office action mailed 11/21/2024) teach that short of mutational studies of all possible amino acid substitutions for a protein, coupled with comprehensive functional assays, the sheer number and diversity of missense mutations that are possible for proteins means that their functional importance must presently be addressed primarily by computational inference (see e.g. page E5189, left column). However, in a study examining some of these methods, Miosge shows that there is potential for incorrect calling of mutations (see e.g. page E5196, left column, top paragraph). The authors conclude that the discordance between predicted and actual effect of missense mutations creates the potential for many false conclusions in clinical settings where sequencing is performed to detect disease-causing mutations (see e.g. page E5195, right column, last paragraph). The findings in their study show underscore the importance of interpreting variation by direct experimental measurement of the consequences of a candidate mutation, using as sensitive and specific an assay as possible (see e.g. page E5197, left column, top paragraph). Additionally, Bork (Genome Research, 2000,10:398-400); previously submitted with the Office action mailed 11/21/2024) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
One key issue is the prediction of protein function based on sequence similarity, which could be one way to identify the functional proteins that are useful in the instant claims. Kulmanov et al (Bioinformatics, 34(4), 2018, 660–668); previously submitted with the Office action mailed 11/21/2024), teach that there are key challenges for protein function prediction methods (see e.g. page 661, left column). These challenges arise from the difficulty identifying and accounting for the complex relationship between protein sequence structure and function (see e.g. page 661, left column). Despite significant progress in the past years in protein structure prediction, it still requires large efforts to predict protein structure with sufficient quality to be useful in function prediction (see e.g. page 661, left column). Another challenge is that proteins do not function in isolation. In particular higher level physiological functions that go beyond simple molecular interactions will require other proteins and cannot usually be predicted by considering a single protein in isolation (see e.g. page 661, left column). Due to these challenges it is not obvious what kinds of features should be used to predict the functions of a protein and whether they can be generated efficiently for a large number of proteins, such as the vast genus of proteins and peptides that may be encompassed by the instant claims (see e.g. page 661, left column).
The state of the art regarding the structure-function correlation cannot be relied upon because functional characteristics of any peptide/protein are determined by its structure as evidenced by Greenspan et al. 1999 (Defining epitopes: It's not as easy as it seems; Nature Biotechnology, 17:936-937); previously submitted with the Office action mailed 11/21/2024). Greenspan et al. teach that as little as one substitution of an amino acid (e.g. alanine) in a sequence results in unpredictable changes in the 3-dimenstional structure of the new peptide sequence which, in turn, results in changes in the functional activity such as binding affinity of the peptide sequence (page 936, 1st column). Greenspan et al. teach that contribution of each residue (i.e. each amino acid) cannot be estimated with any confidence if the replacement affects the properties of the free form of the molecule (page 936, 3rd column).
Given not only the teachings of Skolnick et al., Lazar et al., Burgess et al., and Greenspan et al., but also the limitations and pitfalls of using computational sequence analysis and the unknown effects of alternative splicing, post translational modification and cellular context on protein function as taught by Bork, the claimed CARs could not be predicted based on sequence identity. Clearly, it could not be predicted that a polypeptide or a variant that shares only partial homology with a disclosed protein or that is a fragment of a given SEQ ID NO. will function in a given manner.
The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function (see MPEP 2163). A patent specification must set forth enough detail to allow a person of ordinary skill in the art to understand what is claimed and to recognize that the inventor invented what is claimed. In the case of CARs, an adequate written description requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention (see Lilly, 119 F.3d at 1566 (quoting Fiers, 984 F.2d 15 1171 ). Because the specification does not describe the amino acid sequences nor any core structures for potentially numerous different antibody amino acid sequences which would have the recited dissociation constant, one of skill in the art would reasonably conclude that applicant was not in possession of the claimed genus of all CARs.
A key role played by the written description requirement is to prevent “attempt[s] to preempt the future before it has arrived.” Ariad at 1353, (quoting Fiers v. Revel, 984 F.2d at 1171). Upholding a patent drawn to a genus of antibodies that includes members not previously characterized or described could negatively impact the future development of species within the claimed genus of antibodies.
While "examples explicitly covering the full scope of the claim language" typically will not be required, a sufficient number of representative species must be included to "demonstrate that the patentee possessed the full scope of the [claimed] invention." Lizard tech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1345, 76 USPQ2d 1724,1732 (Fed. Cir. 2005).
In the absence of sufficient recitation of distinguishing characteristics, the specification does not provide adequate written description of the claimed genus. One of skill in the art would not recognize from the disclosure that the applicant was in possession of the claimed CARs. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features (see, Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916,927, 69 USPQ2d 1886, 1895 (Fed. Cir. 2004); accord Ex Parte Kubin, 2007-0819, BPAI 31 May 2007, opinion at p. 16, paragraph 1). The specification does not clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed (see Vas-Cath at page 1116).
Without an adequate structural description of the claimed components and descriptive support on how to put them together, one of ordinary skill in the art would not be reasonably apprised that Applicant was in possession of the genus of CARs as claimed. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (see page 1115).
Applicant’s Arguments
Applicant respectfully disagrees with the written description rejection (see pages 5-9 of the Remarks filed on 10/29/2025).
Applicant restates, as it relates to the specification’s disclosure that the CART cells are made from the CD34- fraction of the mobilized peripheral blood as stated in the claims, that the specification informs one of ordinary skill in the art that “CAR T-cells using … [enriched CD4/8 T-cells after G-CSF mobilization (mob) cells] starting cells were manufactured …” and the CD4/8 enrichment “to deplete myeloid cells by positive selection of T-cells” was performed on the CD34- fraction of the mobilized apheresis product that remained following the CD34+ enrichment step by positive selection…with respect to the Examiner’s asserted grounds for rejection that the specification does not provide guidance or the steps of generating the genus of CARs from CD34 negative cells… the specification teaches that the claimed invention is not directed to a CAR per se, nor to a CAR's use per se. Rather, the specification teaches that the invention as claimed is directed to the discovery that G-CSF-mobilized blood could be a source for T lymphocytes for preparing CAR-T cell for use in adoptive immunotherapy…Thus, the specification “reasonably conveys” that the Applicant “had possession” of the claimed subject matter when the application was filed at least by teaching that T cells obtained from a CD34 negative cell fraction can be used to make CAR T cell by "introducing a nucleic acid comprising a sequence encoding the CAR into a T cell" as specified in claim 1. Besides, the written description requirement does not require actual examples of every embodiment claimed and "it is unnecessary to spell out every detail of the invention ... ; only enough must be included to convince a person of skill in the art that the inventor possessed the invention." Falko- Gunter Falkner v. Inglis, 448 F.3d 1357, 1366 (Fed. Cir. 2006). Indeed, it is accepted that one of ordinary skill in the art at the time of the invention knew how to introduce a nucleic acid comprising a sequence encoding a CAR into a T cell; and the Examiner's rationale that "CAR T- cell therapy is unpredictable" is misplaced and not germane to the invention as claimed. Office Action at page 13, line 9.
Furthermore, without acquiescing the asserted grounds for rejection, claim 5 is amended to incorporate a means-plus-function limitation by reciting "wherein the antigen binding domain comprises means for specifically binding to a CD33 antigen." To satisfy the written description requirement for a means-plus-function limitation, the Applicant only needs to disclose one structure that is capable of carrying out the recited function. See D.MI, Inc. v. Deere & Co., 755 F.2d 1570, 1574 (Fed. Cir. 1985) ("Patentees are required to disclose in the specification some enabling means for accomplishing the function set forth in the 'means plus function' limitation. At the same time, there is and can be no requirement that applicants describe or predict every possible means of accomplishing that function.")… Thus, it is respectfully submitted that one of ordinary skill in the art understands the structure of gemtuzumab monoclonal antibody and that the corresponding structure of the antigen binding domain is adequate to perform the function recited in a means-plus-function limitation. One of ordinary skill in the art would certainly understand that the single chain variable fragment (scFv) of the CAR33 that is based on the anti-CD33 monoclonal antibody gemtuzumab as described in the specification, will perform the function of binding to CD33. Id. Accordingly, those of ordinary skill in the art would understand that the specification's disclosure of gemtuzumab is sufficient to perform the function recited in the limitation "means for specifically binding to CD33" as recited in claim 5. Moreover, that the disclosure of gemtuzumab monoclonal antibody in the specification is sufficient to provide adequate structure corresponding to the "means for specifically binding to CD33" such that the written description requirement is satisfied is supported by the Appellate Review Panel (ARP) decision for In re Xencor. See, e.g., Appeals Review Panel Decision of the Patent Trial and Appeal Board mailed on May 21, 2024, No. 2022-001944, at page 31, line 8 through page 33, line 17. In re Xencor involved U.S. Patent Application No. 16/803,690, and the Examiner and subsequently the Board had rejected claim 9 on written description grounds based in part on the recitation of "means for binding human CS protein." Appellant had argued that the term 5G1.1 refers to both the murine and humanized version of 5G1.1 and includes eculizumab and, thus, satisfies the written description requirement… Moreover, the United States Court of Appeals for the Federal Circuit (Fed. Circ.) decision for In re Xencor (appealed on other grounds) tacitly accepted the ARP ruling on the sufficiency of written description of the means for binding limitation in that case, writing that the means plus function claim in question "is limited to the anti-CS antibody 5G1.1 and equivalents thereof...". In re: Xencor, Inc., Appeal No. 2024-1870, Decided March 13, 2025 (Fed. Circ.).
Response to Arguments
Applicant's arguments filed 10/29/2025 have been fully considered but they are not persuasive.
As stated above, Examiner acknowledges that the specification does provide support for generating CAR33 T cells from the CD34- fraction (see Example 2; page 56, lines 6-13), however, the claims are not limited to this species. While Applicant is entitled to use functional language in the description of claimed agents, according to MPEP 2163, an invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. This matches the facts here. The claims require specific functionality for the components of the CAR (e.g., an intracellular signaling domain and a transmembrane domain), but neither the instant disclosure, nor the art, provide description of the corresponding structure for that functionality or a representative number of species for the components. In both the base claims and the dependent claims, for at least one component in each claim, the claims only describe what the component does, not what the components are.
There are thousands of possible CARs encompassed by the instant claims. One of skill in the art could not immediately envisage the encompassed species in each genus from the guidance provided in the instant specification and claims. Applicant has supplied a single species of CARs, which is a second-generation CAR with a 41BB co-stimulatory domain and a scFv that is based on the anti-CD33 monoclonal antibody gemtuzumab. However, the claims are not limited to this species. The claims encompass all CARs that can be generated from a CD34 negative cell fraction of the mobilized peripheral blood of the subject. This encompasses an extremely broad genus of peptides, for which no correlating structure is provided. While one of skill in the art could likely screen for said peptides, the mere fact that experimentation is necessary to identify the members of the genus indicates that proper description has not been provided.
The Federal Circuit has explained that a specification cannot always support expansive claim language and satisfy the requirements of 35 U.S.C. 112 "merely by clearly describing one embodiment of the thing claimed." LizardTech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1346, 76 USPQ2d 1731, 1733 (Fed. Cir. 2005). Describing a composition by its function alone typically will not suffice to sufficiently describe the composition. See Eli Lilly, 119 F.3 at 1568, 43 USPQ2d at 1406 (Holding that description of a gene' s function will not enable claims to the gene "because it is only an indication of what the gene does, rather than what it is."); see also Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991)). An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004) (The patent at issue claimed a method of selectively inhibiting PGHS-2 activity by administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product, however the patent did not disclose any compounds that can be used in the claimed methods. While there was a description of assays for screening compounds to identify those that inhibit the expression or activity of the PGHS-2 gene product, there was no disclosure of which peptides, polynucleotides, and small organic molecules selectively inhibit PGHS-2. The court held that "[w]ithout such disclosure, the claimed methods cannot be said to have been described.").
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. Further, arguments relating to the isolation of an antibody with specific characteristics may be more appropriately directed to the invention' s enablement, since the method of isolating would detail how to make the invention. However, the enablement of the invention has not been rejected by the Examiner.
Regarding Applicant’s argument related to the use of CAR-T cells for use in adoptive immunotherapy; this argument is related to enablement of the invention. Applicant is reminded that the written description requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc); Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1560, 19 USPQ2d 1111, 1114 (Fed. Cir. 1991). However, as referenced in the previous action mailed 08/01/2025, the Board in Capon v. Eshhar had ruled that the exact nucleotide sequences must be presented for the product, despite both parties stating that a person of skill in the art would know that the DNA segments would retain DNA sequences when linked by known methods. The court even specifically points out that “The chimeric genes here at issue are prepared from known DNA sequences of known function.” Additionally, the Director argued that it cannot be known whether all of the permutations and combinations covered by the claims will be effective for the intended purpose, and that the claims are too broad because they may include inoperative species. As such, the claims fail to comply with the written description requirement because the specification fails to “reasonably convey” that the applicant invented or had possession of the claimed subject matter when the application was filed.
Examiner acknowledges the means-plus-function language of claim 5. Because this claim limitation is being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, it is being interpreted to cover only the corresponding structure, material, or acts described in the specification as performing the claimed function, and equivalents thereof. Specifically, this claim limitation is being interpreted to cover gemtuzumab, an anti-CD33 monoclonal antibody, as described in the specification (see Example 2; page 56, lines 6-13). As such, adequate written description is provided for this limitation.
As such, the written description rejection is maintained for claims 1 and 15, and new claim 73.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANAYA L MIDDLETON whose telephone number is (571)270-5479. The examiner can normally be reached M-F 9:30AM - 6PM with flex.
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/DANAYA L MIDDLETON/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674