Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on June 25, 2026 has been entered.
Detailed Action
This action is in response to the papers filed June 25, 2026.
Amendments
Applicant's response and amendments, filed June 25, 2026, are acknowledged. Applicant has cancelled Claims 1-107, 116, 121, 123-126, and 128-129, amended Claims 108-112, 115, 117-120, 122, and 127, withdrawn Claims 109-110, 112-113, 122, and 127, and added new claims, Claims 130-131.
Claims 108-115, 117-120, 122, 127, and 130-131 are pending.
Election/Restrictions
Applicant has elected the following species, wherein:
i) the alternative mRNA modification is “adding a 5’ cap to the mRNA”, as recited in Claim 111;
ii) the alternative CAR antigen binding domain is a HER2 binding domain, as recited in Claims 117 and 120(a);
iii) the alternative CAR intracellular domain is an intracellular signaling domain from FcalphaR, as recited in Claims 118 and 120(c);
iv) the alternative CAR transmembrane domain is a transmembrane domain of CD89, as recited in Claims 119(b) and 120(b);
v) the alternative host immune cell is CD14+ and CD16-, as recited in Claims 121 and 124;
vi) the alternative additional method step further comprises (d) culturing the engineered immune cell in the presence of one or more cytokines, as recited in Claim 126; and
vii) alternative phenotypic response is “exhibits increased phagocytosis compared to ... unmodified mRNA”, as recited in Claim 129.
Claims 108-115, 117-120, 122, 127, and 130-131 are pending.
Claims 109-110, 112-113, 122, and 127 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 108, 111, 114-115, 117-120, and 130-131 are under consideration.
Priority
This application is a continuation of PCT/US2020/064686 filed on December 11, 2020, which is a continuation of application 16/826,708 filed on March 23, 2020, now U.S. Patent 10,980,836. Applicant’s claim for the benefit of a prior-filed application provisional applications:
63/014,068 filed on April 22, 2020;
63/003,617 filed on April 1, 2020; and
62/946,896 filed on December 11, 2019,
under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994)
The disclosure of the prior-filed applications 62/946,896 filed on December 11, 2019 and 63/003,617 filed on April 1, 2020 fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
While Claim 108 has been amended to recite a population of cells comprising human CD14+ myeloid cells, the claim does not recite wherein the subject is a human subject. Thus, the breadth of the claims reasonably encompasses non-human animal xenograft models comprising human CD14+ myeloid cells.
United States Court of Appeals for the Federal Circuit, Regents of the University of Minnesota v. Gilead Sciences, Inc (Case 21-2168; decided March 6, 2023).
Written description of a broad genus requires description not only of the outer limits of the genus but also of either a representative number of members of the genus or structural features common to the members of the genus, in either case with enough precision that a relevant artisan can visualize or recognize the members of the genus. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1350−52 (Fed. Cir. 2010) (en banc). A broad outline of a genus’s perimeter is insufficient. See id.
Original disclosure may not be relied upon unless it “constitute[s] a full, clear, concise and exact description” of the invention claimed in the patent to one of ordinary skill. In re Wertheim, 646 F.2d 527, 538–39 (CCPA 1981).
For genus claims, which are present here, we have looked for blaze marks within the disclosure that guide attention to the claimed species or subgenus. In re Ruschig, 379 F.2d 990, 994–95 (CCPA 1967); Fujikawa v. Wattana-sin, 93 F.3d 1559, 1571 (Fed. Cir. 1996); see also Purdue Pharma L.P. v. Faulding Inc., 230 F.3d 1320, 1326–27 (Fed. Cir. 2000).
Following this maze-like path, each step providing multiple alternative paths, is not a written description of what might have been described if each of the optional steps had been set forth as the only option. This argument calls to mind what Yogi Berra, the Yankee catcher, was reported to have said: “when one comes to a fork in the road, take it.” That comment was notable because of its indeterminacy, its lack of direction. Similarly, here, all those optional choices do not define the intended result of the instant combination of specific method step parameters.
Clearly, however, just because a moiety is listed as one possible choice for one position does not mean there is ipsis verbis support for every species or sub-genus that chooses that moiety. Were this the case, a “laundry list” disclosure of every possible moiety for every possible position would constitute a written description of every species in the genus. This cannot be because such a disclosure would not “reasonably lead” those skilled in the art to any particular species.
Indeed, the listings of possibilities are so long, and so interwoven, that it is quite unclear how many compounds actually fall within the described genera and subgenera.
As explained by the Board, “[t]hese blaze marks must be clear because ‘it is easy to bypass a tree in the forest, even one that lies close to the trail.’” Decision at *10 (citing Fujikawa, 93 F.3d at 1571).
The Board concluded that, “[i]n this case, we find the point at which one must leave the trail to find the tree is not well marked in:
[62/946,896 filed on December 11, 2019];
[63/003,617 filed on April 1, 2020];
[63/014,068 filed on April 22, 2020]; and/or
[PCT/US2020/064686 filed on December 11, 2020],
do not provide sufficient written description support for the sub-genus of challenged claim 1.” Decision at *10.
The ‘896 application fails to disclose an in vivo method of modifying human CD14+ myeloid cells in a subject comprising the step of administering to a subject a pharmaceutical composition comprising a lipid nanoparticle encapsulating the modified mRNA encoding a chimeric antigen receptor (CAR), nor non-human animal xenograft models comprising human CD14+ myeloid cells.
While ‘896 application discloses a population of cells comprising CD14+ cells comprises less than 10% dendritic cells (e.g. [0014]), ‘896 does not disclose this population also comprises at least 50% of which are human CD14+, CD16- myeloid cells, as now recited in currently amended Claim 108.
While ‘896 application discloses a population of cells comprising CD14+ cells comprises at least 50% of which are CD14+, CD16- myeloid cells (e.g. [0075]), ‘896 does not disclose this population also comprises less than 10% dendritic cells, as now recited in currently amended Claim 108. Furthermore, such disclosure is in the context of engineered cells produced ex vivo, per “population of myeloid cells for cell therapy”, not in vivo production of engineered cells, as encompassed by Claim 108, and claims dependent therefrom.
While ‘896 discloses the chimeric antigen receptor may comprise a FcR-alpha transmembrane domain (e.g. [0179]), such disclosure is in the context of a laundry list of transmembrane domains. There is no example or reduction to practice using this particular embodiment. It is disclosed only once in boiler plate format.
The disclosure of 62/946,896 fails to provide ipsis verbis support nor sufficient blaze marks to guide the skilled artisan to the combination of limitations, and/or subcombinations thereof, presently recited in independent Claim 108, and claims dependent therefrom, of the instant application.
The ‘617 application fails to disclose an in vivo method of modifying human CD14+ myeloid cells in a subject comprising the step of administering to a subject a pharmaceutical composition comprising a lipid nanoparticle encapsulating the modified mRNA encoding a chimeric antigen receptor (CAR), nor non-human animal xenograft models comprising human CD14+ myeloid cells.
While ‘617 discloses that CD14+ myeloid cells may be administered systemically to a subject (e.g. [0210]), ‘617 is silent to the instantly recited method steps of administering to a subject a pharmaceutical composition comprising a lipid nanoparticle encapsulating the modified mRNA encoding a chimeric antigen receptor (CAR).
‘617 is silent to “intravenous”, as recited in instant Claim 115.
While ‘617 application discloses a population of cells comprising CD14+ cells comprises less than 10% dendritic cells (e.g. [0011, 89]), ‘617 does not disclose this population also comprises at least 50% of which are human CD14+, CD16- myeloid cells, as now recited in currently amended Claim 108. Furthermore, such disclosure is in the context of engineered cells produced ex vivo, per “a pharmaceutical composition comprising”, not in vivo production of engineered cells, as encompassed by Claim 108, and claims dependent therefrom.
While ‘617 application discloses a population of cells comprising CD14+ cells comprises at least 50% of which are CD14+, CD16- myeloid cells (e.g. [0073]), ‘617 does not disclose this population also comprises less than 10% dendritic cells, as now recited in currently amended Claim 108. Furthermore, such disclosure is in the context of engineered cells produced ex vivo, per “population of myeloid cells for cell therapy”, not in vivo production of engineered cells, as encompassed by Claim 108, and claims dependent therefrom.
While ‘617 discloses the chimeric antigen receptor may comprise a FcR-alpha transmembrane domain (e.g. [0221]), such disclosure is in the context of a laundry list of transmembrane domains. There is no example or reduction to practice using this particular embodiment. It is disclosed only once in boiler plate format.
The disclosure of 63/003,617 fails to provide ipsis verbis support nor sufficient blaze marks to guide the skilled artisan to the combination of limitations, and/or subcombinations thereof, presently recited in independent Claim 108, and claims dependent therefrom, of the instant application.
The ‘068 application fails to disclose an in vivo method of modifying human CD14+ myeloid cells in a subject comprising the step of administering to the subject a pharmaceutical composition comprising a lipid nanoparticle encapsulating the modified mRNA encoding a chimeric antigen receptor (CAR), nor non-human animal xenograft models comprising human CD14+ myeloid cells.
While ‘068 does support administering a LNP encapsulating a RNA to a subject (e.g. pgs 59-60), wherein the RNA encodes a chimeric antigen receptor (e.g. pg 7, [0058-61]), and that the nucleic acid pharmaceutical is injected intravenously to the subject (e.g. [0252]), instant Claim 108 is broader in scope than intravenous administration (instant Claim 115), as it encompasses routes of administration other than intravenous, support for which cannot be found in ‘068. The term “systemic” is disclosed only in the context of administering myeloid cells to a subject (e.g. pg 40, [0234]).
While ‘068 application discloses a population of cells comprising CD14+ cells comprises:
at least 50% of which are CD14+, CD16- myeloid cells; and
less than 10% dendritic cells (e.g. [0091]),
such disclosure is in the context of engineered cells produced ex vivo, per “a pharmaceutical composition comprising”, not in vivo production of engineered cells, as encompassed by Claim 108, and claims dependent therefrom.
While ‘068 discloses the chimeric antigen receptor may comprise a FcR-alpha transmembrane domain (e.g. [0245]), such disclosure is in the context of a laundry list of transmembrane domains. There is no example or reduction to practice using this particular embodiment. It is disclosed only once in boiler plate format.
The disclosure of 63/014,068 fails to provide ipsis verbis support nor sufficient blaze marks to guide the skilled artisan to the combination of limitations, and/or subcombinations thereof, presently recited in independent Claim 108, and claims dependent therefrom, of the instant application.
The PCT/US2020/064686 application fails to disclose an in vivo method of modifying human CD14+ myeloid cells in a subject comprising the step of systemically administering to the subject a pharmaceutical composition comprising a lipid nanoparticle encapsulating the modified mRNA encoding a chimeric antigen receptor (CAR), nor non-human animal xenograft models comprising human CD14+ myeloid cells.
While ‘686 does support administering intravenously to a subject a composition comprising RNA (e.g. pg 67, [0372-373]), wherein the RNA encodes a chimeric antigen receptor (e.g. pg 9, [0074]), instant Claim 108 is broader in scope than intravenous administration (instant Claim 115), as it encompasses routes of administration other than intravenous, support for which cannot be found in ‘686. The term “systemic” is disclosed only in the context of administering myeloid cells to a subject (e.g. pg 18, [0161]).
While ‘686 application discloses a population of cells comprising CD14+ cells comprises:
at least 50% of which are CD14+, CD16- myeloid cells; and
less than 10% dendritic cells (e.g. [0030]),
such disclosure is in the context of engineered cells produced ex vivo, per “the ex vivo population of huma cells”, not in vivo production of engineered cells, as encompassed by Claim 108, and claims dependent therefrom.
‘686 fails to disclose the chimeric antigen receptor may comprise a FcR-alpha transmembrane domain. There is no example or reduction to practice using this particular embodiment. Rather, it is directed to a CD8, CD28, or CD68 transmembrane domain (e.g. [0017]; pgs 53-54, Table 1; Figure 16B).
The disclosure of PCT/US2020/064686 fails to provide ipsis verbis support nor sufficient blaze marks to guide the skilled artisan to the combination of limitations, and/or subcombinations thereof, presently recited in independent Claim 108, and claims dependent therefrom, of the instant application.
Instant application suffers the same deficiencies as 62/946,896 filed on December 11, 2019, 63/003,617 filed on April 1, 2020, 63/014,068 filed on April 22, 2020, and/or PCT/US2020/064686 filed on December 11, 2020.
Accordingly, the effective priority date of the claims is granted as the filing date of the instant application, June 10, 2022, the filing date of the instant application.
If Applicant believes the earlier applications and/or instant application provide support for non-human animal xenograft models comprising human CD14+ myeloid cells, Applicant should point out such support with particularity by page and line number in the reply to this Action.
Response to Arguments
Applicant argues that ‘896 [00164], pg. 23, discloses engineering of myeloid cells with exogenous agents.
Applicant’s argument(s) has been fully considered, but is not persuasive. Instant Claim 108 encompasses in vivo modification of human myeloid cells. The ‘896 application fails to disclose an in vivo method of modifying human CD14+ myeloid cells in a subject comprising the step of systemically administering to a subject a pharmaceutical composition comprising a lipid nanoparticle encapsulating the modified mRNA encoding a chimeric antigen receptor (CAR), nor non-human animal xenograft models comprising human CD14+ myeloid cells.
‘896 [00164] fails to make up for these deficiencies.
Applicant argues that 896 [0028], pg. 4, discloses that the exogenous agent can be a lipid and can comprise a nucleic acid sequence encoding a CAR.
Applicant’s argument(s) has been fully considered, but is not persuasive. The ‘896 application fails to disclose an in vivo method of modifying human CD14+ myeloid cells in a subject comprising the step of systemically administering to a subject a pharmaceutical composition comprising a lipid nanoparticle encapsulating the modified mRNA encoding a chimeric antigen receptor (CAR), nor non-human animal xenograft models comprising human CD14+ myeloid cells.
‘896 [0028] fails to make up for these deficiencies.
Applicant argues that ‘896 [00179], pg. 26, discloses that the CAR can comprise a transmembrane domain from FcR-alpha.
Applicant’s argument(s) has been fully considered, but is not persuasive. The ‘896 application fails to disclose an in vivo method of modifying human CD14+ myeloid cells in a subject comprising the step of systemically administering to a subject a pharmaceutical composition comprising a lipid nanoparticle encapsulating the modified mRNA encoding a chimeric antigen receptor (CAR), nor non-human animal xenograft models comprising human CD14+ myeloid cells.
‘896 [00179] fails to make up for these deficiencies.
Applicant argues that ‘896 [00186], pg. 28, discloses frequencies of CD14 expression.
Applicant’s argument(s) has been fully considered, but is not persuasive. The ‘896 application fails to disclose an in vivo method of modifying human CD14+ myeloid cells in a subject comprising the step of systemically administering to a subject a pharmaceutical composition comprising a lipid nanoparticle encapsulating the modified mRNA encoding a chimeric antigen receptor (CAR), nor non-human animal xenograft models comprising human CD14+ myeloid cells.
‘896 [00186] fails to make up for these deficiencies.
Applicant argues that Claim 2 of '896 discloses that the frequency of dendritic cells in the population is less than 10%.
Applicant’s argument(s) has been fully considered, but is not persuasive. The ‘896 application fails to disclose an in vivo method of modifying human CD14+ myeloid cells in a subject comprising the step of systemically administering to a subject a pharmaceutical composition comprising a lipid nanoparticle encapsulating the modified mRNA encoding a chimeric antigen receptor (CAR), nor non-human animal xenograft models comprising human CD14+ myeloid cells.
‘896 claim 2 fails to make up for these deficiencies.
Applicant argues that support for an in vivo method is provided in 62/946,896 filed on December 11, 2019 because it discloses culturing cells in vitro.
Applicant’s argument(s) has been fully considered, but is not persuasive. Applicant fails to point out with particularity such support for the instantly claimed method is provided in each of the respective priority documents.
Information Disclosure Statement
Applicant has filed an Information Disclosure Statement on June 25, 2026 that has been considered.
The signed and initialed PTO Forms 1449 are mailed with this action.
Claim Objections
1. Claim 108 is objected to because of the following informalities:
Where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation, 37 CFR 1.75(i). See MPEP §608.01(m).
Embodiments (a) and (b) should be separated by punctuation, e.g. a comma or semi-colon, and line indentation.
Appropriate correction is required. See, for example, Claim 120.
Claim Rejections - 35 USC § 112
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.
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.
2. The prior rejection of Claim 115 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, is withdrawn in light of Applicant’s amendment to independent Claim 108, which the Examiner finds persuasive.
3. The prior rejection of Claim 116 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, is withdrawn in light of Applicant’s cancellation of the claim.
4. The prior rejection of Claim(s) 116-120 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is withdrawn in light of Applicant’s cancellation of Claim 116, and amending Claims 117-120 to become dependent upon independent Claim 108, which the Examiner finds persuasive.
5. The prior rejection of Claims 108, 111, 114-120, and 124 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of Applicant’s amendments to Claim 108, which the Examiner finds persuasive.
6. Claim 115 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 15 has been amended to recite “administering” in reference to Claim 108. There is insufficient antecedent basis for this limitation in the claim because independent Claim 108 does not recite an administering step.
Appropriate correction is required.
7. Claim 115 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 15 has been amended to recite “administering comprises delivery by intravenous injection”.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, Claim 15 recites the broad recitation “administering comprises delivery”, and the claim also recites “intravenous injection” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
The term "comprises" is open-ended and allows for additional, unrecited elements in the claims. MPEP 2111.03 specifically sets forth that the transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004). While it is clear that intravenous injection is one embodiment of “administering comprises delivery by”, the metes and bounds of the claim are unclear because the claim fails to recite what other anatomical routes objectively fall within “administering comprises delivery by”, as opposed to what other anatomical routes are objectively excluded from “administering comprises delivery by”.
As discussed in the prior Office Action, the claimed method of delivering and/or administering is recited at a high level of generality for the multitude of anatomically distinct administration routes, including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, alimentary, ingestion, inhalation, mucosal, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, otopically, transdermally, dermal, intradermal, subcutaneously, parenterally, transmucosally, rectally, intracavity, intraglandular, intra-pleurally, intraperitoneally, intravenously, intrarterial, intravascular, intramuscularly, intracranially, intra-spinal, intrathecal, iontophoretic, intraocular, ophthalmic, optical, intraorgan, or intralymphatic (e.g. High et al (U.S. 2015/0111955, [0077]; of record).
The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
The Examiner suggests amending the claim to instead recite, ‘wherein the mRNA encapsulated in a lipid nanoparticle (LNP) is administered to the subject by intravenous injection’, for example.
8. Claims 108, 111, 114-115, 117-120, and 130 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.
Claim 108 has been amended to recite a method of modifying a human CD14+ myeloid cell with modified mRNA, the method comprising the step of contacting the human CD14+ myeloid cells with a pharmaceutical composition comprising a lipid nanoparticle encapsulating the modified mRNA encoding a chimeric antigen receptor (CAR).
While independent Claim 108 has been amended to cancel ipsis verbis recitation of “in vivo” and “delivering”, the breadth of the claim continues to read upon in vivo contexts, as discussed in the prior Office Action.
See dependent Claim 115, “intravenous injection”.
Contrast with newly presented dependent Claim 131 reciting the method is limited to an “ex vivo” context.
As discussed previously, the claim does not recite wherein the subject is a human subject. Thus, the breadth of the claims reasonably encompasses non-human animal xenograft models comprising human CD14+ myeloid cells.
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 by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
Parameter 1
Claim 108 does not recite wherein the subject is a human subject. Thus, the breadth of the claims reasonably encompasses non-human animal xenograft models comprising human CD14+ myeloid cells.
The claims are broad for reasonably encompassing about 1,000,000 species of animals (Kingdoms of Life, waynesword.palomar.edu/trfeb98.htm, last visited April 8, 2021), wherein the mammalian sub-genus reasonably encompasses some 6,400 species (including humans), distributed in about 1,200 genera, about 152 families and about 29 orders (Mammal, en.wikipedia.org/wiki/Mammal, last visited August 31, 2022).
Parameter 2
The claimed method of delivering is recited at a high level of generality for the multitude of anatomically distinct administration routes, including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, alimentary, ingestion, inhalation, mucosal, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, otopically, transdermally, dermal, intradermal, subcutaneously, parenterally, transmucosally, rectally, intracavity, intraglandular, intra-pleurally, intraperitoneally, intravenously, intrarterial, intravascular, intramuscularly, intracranially, intra-spinal, intrathecal, iontophoretic, intraocular, ophthalmic, optical, intraorgan, or intralymphatic (e.g. High et al (U.S. 2015/0111955, [0077]; of record).
At best, the specification discloses intravenous administration of the nucleic acid, e.g. [0373].
Parameter 3
The claims are broad for failing to recite the dosage of the LNP encapsulating the mRNA encoding the chimeric antigen receptor that is to be administered via the broadly claimed [parameter 2] genus of anatomically distinct routes to the broadly claimed [parameter 1] genus of about 1x10^6 human and non-human animal subjects.
The claim fails to recite, and the specification fails to disclose, a first xenograft animal subject whose body necessarily and predictably comprises a population of cells:
a) at least 50% of which are human CD14+, CD16- myeloid cells; and
b) less than 10% of the human CD14+ myeloid cells are dendritic cells, as opposed to a second xenograft animal subject whose body does not necessarily and predictably comprise a population of cells:
a) at least 50% of which are human CD14+, CD16- myeloid cells; and/or
b) less than 10% of the human CD14+ myeloid cells are dendritic cells, for example.
The claim fails to recite, and the specification fails to disclose, a first xenograft animal subject whose body necessarily and predictably comprises a population of cells:
a) at least 30%, but not 40% or 50%, of which are human CD14+, CD16- myeloid cells; and
b) less than 5%, but not 7% or 10%, of the human CD14+ myeloid cells are dendritic cells, for example.
The claim fails to recite, and the specification fails to disclose, a first LNP-mRNA dosage [parameter 3] administered via a first administration route [parameter 2], e.g. inhalation, to a first xenograft animal of the 1x10^6 subjects [parameter 1], e.g. sheep, whose body necessarily and predictably comprises a population of cells:
a) at least 50% of which are human CD14+, CD16- myeloid cells; and
b) less than 10% of the human CD14+ myeloid cells are dendritic cells,
thereby engineering a human myeloid cell with the mRNA encoding the CAR, as opposed to
a second LNP-mRNA dosage [parameter 3] administered via a second administration route [parameter 2], e.g. ophthalmic injection, to a second xenograft animal of the 1x10^6 subjects [parameter 1], e.g. lizard, whose body necessarily and predictably comprises a population of cells:
a) at least 50% of which are human CD14+, CD16- myeloid cells; and
b) less than 10% of the human CD14+ myeloid cells are dendritic cells,
thereby necessarily and predictably engineering a human myeloid cell with the mRNA encoding the CAR, for example.
The claim fails to recite, and the specification fails to disclose, how to transform or otherwise modify a first LNP-mRNA dosage [parameter 3] administered via a first administration route [parameter 2], e.g. intrathecal injection, to a first xenograft animal of the 1x10^6 subjects [parameter 1], e.g. a guinea pig, whose body necessarily and predictably comprises a population of cells:
a) at least 50% of which are human CD14+, CD16- myeloid cells; and
b) less than 10% of the human CD14+ myeloid cells are dendritic cells,
that does not necessarily and predictably result in an engineered human myeloid cell with the mRNA encoding the CAR, into
a second LNP-mRNA dosage [parameter 3] administered via a second administration route [parameter 2], e.g. ingestion, to a second xenograft animal of the 1x10^6 subjects [parameter 1], e.g. canine, whose body necessarily and predictably comprises a population of cells:
a) at least 50% of which are human CD14+, CD16- myeloid cells; and
b) less than 10% of the human CD14+ myeloid cells are dendritic cells,
thereby necessarily and predictably engineering a human myeloid cell with the mRNA encoding the CAR, for example.
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This 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)
Dependent claims are included in the basis of the rejection because they do not clarify the nature of the corresponding structure that is necessary and sufficient to cause the recited functional language.
Response to Arguments
Applicant argues that Claim 108 has been amended to cancel recitation of “systemic delivery”.
Applicant’s argument(s) has been fully considered, but is not persuasive. Applicant’s amendment does nothing for the issues of [parameter 1], [parameter 2], and [parameter 3] discussed in the rejection.
Applicant argues that instant specification provides support for an in vivo method comprising systemic administration.
Applicant’s argument(s) has been fully considered, but is not persuasive. While instant specification provides support for intravenous administration, e.g. [0373], instantly recited “systemic delivery” is not supported by the priority documents nor instant application. See discussion above in Priority section.
If Applicant believes the earlier applications and/or instant application provide support for non-human animal xenograft models comprising human CD14+ myeloid cells, Applicant should point out such support with particularity by page and line number in the reply to this Action.
New Matter
9. Claim(s) 108, 111, 114-115, 117-120, and 130-131 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim(s) 108 has been amended to recite wherein the chimeric antigen receptor comprises a FcR-alpha transmembrane domain. Clear support for the new limitation(s) cannot be found in the instant application or priority documents. Accordingly, the amendment(s) to Claim(s) 108 is/are considered to constitute new matter.
MPEP 2163.06 notes “If new matter is added to the claims, the examiner should reject the claims under 35 U.S.C. 112, first paragraph - written description requirement. In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981).” MPEP 2163.02 teaches that “Whenever the issue arises, the fundamental factual inquiry is whether a claim defines an invention that is clearly conveyed to those skilled in the art at the time the application was filed...If a claim is amended to include subject matter, limitations, or terminology not present in the application as filed, involving a departure from, addition to, or deletion from the disclosure of the application as filed, the examiner should conclude that the claimed subject matter is not described in that application”. MPEP 2163.06 further notes “When an amendment is filed in reply to an objection or rejection based on 35 U.S.C. 112, first paragraph, a study of the entire application is often necessary to determine whether or not “new matter” is involved. Applicant should therefore specifically point out the support for any amendments made to the disclosure” (emphasis added).
Applicant argues that support for the new limitation(s) may be found in the originally filed application.
The originally filed application is silent to chimeric antigen receptor comprises a FcR-alpha transmembrane domain.
The Examiner incorporates herein the above Priority discussion.
United States Court of Appeals for the Federal Circuit, Regents of the University of Minnesota v. Gilead Sciences, Inc (Case 21-2168; decided March 6, 2023).
Written description of a broad genus requires description not only of the outer limits of the genus but also of either a representative number of members of the genus or structural features common to the members of the genus, in either case with enough precision that a relevant artisan can visualize or recognize the members of the genus. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1350−52 (Fed. Cir. 2010) (en banc). A broad outline of a genus’s perimeter is insufficient. See id.
Original disclosure may not be relied upon unless it “constitute[s] a full, clear, concise and exact description” of the invention claimed in the patent to one of ordinary skill. In re Wertheim, 646 F.2d 527, 538–39 (CCPA 1981).
For genus claims, which are present here, we have looked for blaze marks within the disclosure that guide attention to the claimed species or subgenus. In re Ruschig, 379 F.2d 990, 994–95 (CCPA 1967); Fujikawa v. Wattana-sin, 93 F.3d 1559, 1571 (Fed. Cir. 1996); see also Purdue Pharma L.P. v. Faulding Inc., 230 F.3d 1320, 1326–27 (Fed. Cir. 2000).
Following this maze-like path, each step providing multiple alternative paths, is not a written description of what might have been described if each of the optional steps had been set forth as the only option. This argument calls to mind what Yogi Berra, the Yankee catcher, was reported to have said: “when one comes to a fork in the road, take it.” That comment was notable because of its indeterminacy, its lack of direction. Similarly, here, all those optional choices do not define the intended result of the instant combination of specific method step parameters.
Clearly, however, just because a moiety is listed as one possible choice for one position does not mean there is ipsis verbis support for every species or sub-genus that chooses that moiety. Were this the case, a “laundry list” disclosure of every possible moiety for every possible position would constitute a written description of every species in the genus. This cannot be because such a disclosure would not “reasonably lead” those skilled in the art to any particular species.
Indeed, the listings of possibilities are so long, and so interwoven, that it is quite unclear how many compounds actually fall within the described genera and subgenera.
As explained by the Board, “[t]hese blaze marks must be clear because ‘it is easy to bypass a tree in the forest, even one that lies close to the trail.’” Decision at *10 (citing Fujikawa, 93 F.3d at 1571).
The Board concluded that, “[i]n this case, we find the point at which one must leave the trail to find the tree is not well marked in:
[62/946,896 filed on December 11, 2019];
[63/003,617 filed on April 1, 2020];
[63/014,068 filed on April 22, 2020]; and/or
[PCT/US2020/064686 filed on December 11, 2020],
do not provide sufficient written description support for the sub-genus of challenged claim 1.” Decision at *10.
The ‘896 application fails to disclose an in vivo method of modifying human CD14+ myeloid cells in a subject comprising the step of administering to a subject a pharmaceutical composition comprising a lipid nanoparticle encapsulating the modified mRNA encoding a chimeric antigen receptor (CAR), nor non-human animal xenograft models comprising human CD14+ myeloid cells.
While ‘896 application discloses a population of cells comprising CD14+ cells comprises less than 10% dendritic cells (e.g. [0014]), ‘896 does not disclose this population also comprises at least 50% of which are human CD14+, CD16- myeloid cells, as now recited in currently amended Claim 108.
While ‘896 application discloses a population of cells comprising CD14+ cells comprises at least 50% of which are CD14+, CD16- myeloid cells (e.g. [0075]), ‘896 does not disclose this population also comprises less than 10% dendritic cells, as now recited in currently amended Claim 108. Furthermore, such disclosure is in the context of engineered cells produced ex vivo, per “population of myeloid cells for cell therapy”, not in vivo production of engineered cells, as encompassed by Claim 108, and claims dependent therefrom.
While ‘896 discloses the chimeric antigen receptor may comprise a FcR-alpha transmembrane domain (e.g. [0179]), such disclosure is in the context of a laundry list of transmembrane domains. There is no example or reduction to practice using this particular embodiment. It is disclosed only once in boiler plate format.
The disclosure of 62/946,896 fails to provide ipsis verbis support nor sufficient blaze marks to guide the skilled artisan to the combination of limitations, and/or subcombinations thereof, presently recited in independent Claim 108, and claims dependent therefrom, of the instant application.
The ‘617 application fails to disclose an in vivo method of modifying human CD14+ myeloid cells in a subject comprising the step of administering to a subject a pharmaceutical composition comprising a lipid nanoparticle encapsulating the modified mRNA encoding a chimeric antigen receptor (CAR), nor non-human animal xenograft models comprising human CD14+ myeloid cells.
While ‘617 discloses that CD14+ myeloid cells may be administered systemically to a subject (e.g. [0210]), ‘617 is silent to the instantly recited method steps of administering to a subject a pharmaceutical composition comprising a lipid nanoparticle encapsulating the modified mRNA encoding a chimeric antigen receptor (CAR).
‘617 is silent to “intravenous”, as recited in instant Claim 115.
While ‘617 application discloses a population of cells comprising CD14+ cells comprises less than 10% dendritic cells (e.g. [0011, 89]), ‘617 does not disclose this population also comprises at least 50% of which are human CD14+, CD16- myeloid cells, as now recited in currently amended Claim 108. Furthermore, such disclosure is in the context of engineered cells produced ex vivo, per “a pharmaceutical composition comprising”, not in vivo production of engineered cells, as encompassed by Claim 108, and claims dependent therefrom.
While ‘617 application discloses a population of cells comprising CD14+ cells comprises at least 50% of which are CD14+, CD16- myeloid cells (e.g. [0073]), ‘617 does not disclose this population also comprises less than 10% dendritic cells, as now recited in currently amended Claim 108. Furthermore, such disclosure is in the context of engineered cells produced ex vivo, per “population of myeloid cells for cell therapy”, not in vivo production of engineered cells, as encompassed by Claim 108, and claims dependent therefrom.
While ‘617 discloses the chimeric antigen receptor may comprise a FcR-alpha transmembrane domain (e.g. [0221]), such disclosure is in the context of a laundry list of transmembrane domains. There is no example or reduction to practice using this particular embodiment. It is disclosed only once in boiler plate format.
The disclosure of 63/003,617 fails to provide ipsis verbis support nor sufficient blaze marks to guide the skilled artisan to the combination of limitations, and/or subcombinations thereof, presently recited in independent Claim 108, and claims dependent therefrom, of the instant application.
The ‘068 application fails to disclose an in vivo method of modifying human CD14+ myeloid cells in a subject comprising the step of administering to the subject a pharmaceutical composition comprising a lipid nanoparticle encapsulating the modified mRNA encoding a chimeric antigen receptor (CAR), nor non-human animal xenograft models comprising human CD14+ myeloid cells.
While ‘068 does support administering a LNP encapsulating a RNA to a subject (e.g. pgs 59-60), wherein the RNA encodes a chimeric antigen receptor (e.g. pg 7, [0058-61]), and that the nucleic acid pharmaceutical is injected intravenously to the subject (e.g. [0252]), instant Claim 108 is broader in scope than intravenous administration (instant Claim 115), as it encompasses routes of administration other than intravenous, support for which cannot be found in ‘068. The term “systemic” is disclosed only in the context of administering myeloid cells to a subject (e.g. pg 40, [0234]).
While ‘068 application discloses a population of cells comprising CD14+ cells comprises:
at least 50% of which are CD14+, CD16- myeloid cells; and
less than 10% dendritic cells (e.g. [0091]),
such disclosure is in the context of engineered cells produced ex vivo, per “a pharmaceutical composition comprising”, not in vivo production of engineered cells, as encompassed by Claim 108, and claims dependent therefrom.
While ‘068 discloses the chimeric antigen receptor may comprise a FcR-alpha transmembrane domain (e.g. [0245]), such disclosure is in the context of a laundry list of transmembrane domains. There is no example or reduction to practice using this particular embodiment. It is disclosed only once in boiler plate format.
The disclosure of 63/014,068 fails to provide ipsis verbis support nor sufficient blaze marks to guide the skilled artisan to the combination of limitations, and/or subcombinations thereof, presently recited in independent Claim 108, and claims dependent therefrom, of the instant application.
The PCT/US2020/064686 application fails to disclose an in vivo method of modifying human CD14+ myeloid cells in a subject comprising the step of systemically administering to the subject a pharmaceutical composition comprising a lipid nanoparticle encapsulating the modified mRNA encoding a chimeric antigen receptor (CAR), nor non-human animal xenograft models comprising human CD14+ myeloid cells.
While ‘686 does support administering intravenously to a subject a composition comprising RNA (e.g. pg 67, [0372-373]), wherein the RNA encodes a chimeric antigen receptor (e.g. pg 9, [0074]), instant Claim 108 is broader in scope than intravenous administration (instant Claim 115), as it encompasses routes of administration other than intravenous, support for which cannot be found in ‘686. The term “systemic” is disclosed only in the context of administering myeloid cells to a subject (e.g. pg 18, [0161]).
While ‘686 application discloses a population of cells comprising CD14+ cells comprises:
at least 50% of which are CD14+, CD16- myeloid cells; and
less than 10% dendritic cells (e.g. [0030]),
such disclosure is in the context of engineered cells produced ex vivo, per “the ex vivo population of huma cells”, not in vivo production of engineered cells, as encompassed by Claim 108, and claims dependent therefrom.
‘686 fails to disclose the chimeric antigen receptor may comprise a FcR-alpha transmembrane domain. There is no example or reduction to practice using this particular embodiment. Rather, it is directed to a CD8, CD28, or CD68 transmembrane domain (e.g. [0017]; pgs 53-54, Table 1; Figure 16B).
The disclosure of PCT/US2020/064686 fails to provide ipsis verbis support nor sufficient blaze marks to guide the skilled artisan to the combination of limitations, and/or subcombinations thereof, presently recited in independent Claim 108, and claims dependent therefrom, of the instant application.
Instant application suffers the same deficiencies as 62/946,896 filed on December 11, 2019, 63/003,617 filed on April 1, 2020, 63/014,068 filed on April 22, 2020, and/or PCT/US2020/064686 filed on December 11, 2020.
The disclosure of instant application fails to provide ipsis verbis support nor sufficient blaze marks to guide the skilled artisan to the combination of limitations, and/or subcombinations thereof, presently recited in independent Claim 108, and claims dependent therefrom, of the instant application.
Alternatively, if Applicant believes that support for the combination of limitations presently recited in independent Claim 108, and claims dependent therefrom, is present and clearly envisaged in the instant application or earlier filed priority documents, applicant must, in responding to this Office Action, point out with particularity, where such support may be found.
Declarations and new references cannot demonstrate possession of a concept after the fact.
Applicant does not indicate where these limitations are supported by the original specification, or how, as is Applicant's burden. See MPEP §714.02, last sentence of the third paragraph from the end and MPEP §2163.06 (I) last sentence.
Claim Rejections - 35 USC § 103
10. The prior rejection of Claims 108, 111, 115-117, 119, and 124 under AIA 35 U.S.C. 103 as being unpatentable over Kauffman et al (2016; of record) in view of Yoon et al (2009; of record), Hung et al (available online May 1, 2018; of record), Google (peripheral blood, CD14+ myeloid; last accessed January 29, 2026; of record), Jabulowsky et al (October 2018; of record), and Morrissey et al (available online June 4, 2018; of record in IDS) is withdrawn in light of Applicant’s amendment to independent Claim 108 introducing New Matter. See 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejection(s) above.
11. The prior rejection of Claims 108, 111, and 114 under AIA 35 U.S.C. 103 as being unpatentable over Kauffman et al (2016; of record) in view of Yoon et al (2009; of record), Hung et al (available online May 1, 2018; of record), Google (of record), Jabulowsky et al (October 2018; of record), and Morrissey et al (available online June 4, 2018; of record in IDS), as applied to Claims 108, 111, 115-117, 119, and 124 above, and in further view of Kariko et al (available online September 2, 2011; of record). is withdrawn in light of Applicant’s amendment to independent Claim 108 introducing New Matter. See 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejection(s) above.
12. The prior rejection of Claims 118-120 under AIA 35 U.S.C. 103 as being unpatentable over Kauffman et al (2016; of record) in view of Yoon et al (2009; of record), Hung et al (available online May 1, 2018; of record), Google (of record), Jabulowsky et al (October 2018; of record), Morrissey et al (available online June 4, 2018; of record in IDS), and Kariko et al (available online September 2, 2011; of record), as applied to Claims 108, 111, 114-117, 119, and 124 above, and in further view of Smith et al (U.S. 2014/0134142; of record), Juillerat et al (U.S. 2017/0073423; of record), and Oda et al (U.S. 2018/0044404; of record) is withdrawn in light of Applicant’s amendment to independent Claim 108 introducing New Matter. See 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejection(s) above.
Citation of Relevant Prior Art
13. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Besin et al (U.S. 2019/0314291; filed January 1, 2019) is considered relevant prior art for having disclosed an mRNA encapsulated by a lipid nanoparticle (e.g. [1381], wherein said mRNA encodes a chimeric antigen receptor (e.g. [0057]).
Besin et al disclosed the CAR transmembrane domain may be derived from FcR-gamma (e.g. [1481]).
Besin et al differs from the instantly claimed invention in that Besin et al do not disclose the CAR to comprise a FcR-alpha transmembrane domain.
Reid et al (U.S. 2021/0163928; priority to at least April 11, 2019) is considered relevant prior art for having disclosed an mRNA encapsulated by a lipid nanoparticle (e.g. [0179, 540, 582, 906], wherein said mRNA encodes a chimeric antigen receptor (e.g. [0904]).
Reid et al differs from the instantly claimed invention in that Reid et al do not disclose the CAR to comprise a FcR-alpha transmembrane domain.
Conclusion
14. No claims are allowed.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638
Prosecution Insights