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 .
Detailed Action
This action is in response to the papers filed January 27, 2026 and February 2, 2026.
Amendments
Applicant's response and amendments, filed January 27, 2026 and February 2, 2026, are acknowledged. Applicant has cancelled Claims 1-107, 121, 125-126, and 129, withdrawn Claims 109-110, 112-113, 122-123, and 127-128, and amended Claims 108, 111, 114-116, 118, 120, 122-124, and 127.
Claims 108-120, 122-124, and 127-128 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 108-120, 122-124, and 127-128 are pending.
Claims 109-110, 112-113, 122-123, and 127-128 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.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, 114-120, and 124 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.
Claim 108 has been amended to recite an in vivo method of modifying a human CD14+ myeloid cell in a subject with modified mRNA, the method comprising the step of systemic delivery to said subject 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 recite a subject 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.
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.
The ‘617 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.
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 systemically 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.
The ‘068 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.
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 that are “systemic”, 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]).
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 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 ‘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 that are “systemic”, 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]).
Accordingly, the effective priority date of the claims is granted as the filing date of the instant application, June 10, 2022.
If Applicant believes the earlier applications and/or instant application provide support for “systemic delivery”, Applicant should point out such support with particularity by page and line number in the reply to this Action.
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 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 January 28, 2026 that has been considered.
The information disclosure statement filed January 28, 2026 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because 37 CFR 1.98(b) requires that each item of information in an IDS be identified properly. Each publication must be identified by publisher, author (if any), title, relevant pages of the publication, and date and place of publication. The date of publication supplied must include at least the month and year of publication, except that the year of publication (without the month) will be accepted if the applicant points out in the information disclosure statement that the year of publication is sufficiently earlier than the effective U.S. filing date and any foreign priority date so that the particular month of publication is not in issue.
See also MPEP 707.05(e) for electronic documents, including, but not limited to:
(D) reference to the unique Digital Object Identifier (DOI) number, or other unique identification number, if known.
NPL citations have been lined through for being defective of one or more requirements.
The signed and initialed PTO Forms 1449 are mailed with this action.
Claim Objections
1. The prior objection to Claims 118-120 is withdrawn in light of Applicant’s amendments to the claims to recite CD89.
2. Claim 21 is objected to because of the following informalities:
As a first matter, 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).
The multiple ‘wherein’ clauses should be separated by line indentation.
As a second matter, instant Claim 118 is unnecessarily verbose.
Claim 118 can instead be drafted more concisely, to wit:
The method of claim 116, wherein the CAR further comprises a CD16a, CD64, CD68, or CD89 intracellular domain.
Appropriate correction is required.
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.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
3. The prior rejection of Claim(s) 108, 111, 114-121, 124-126, and 129 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of Applicant’s amendment to independent Claim 108 to instead recite CD14+ human myeloid cell, and amendment to Claim 118 cancelling recitation of FcalphaR, which the Examiner finds persuasive.
4. The prior rejections of Claim 129 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, and 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, are withdrawn in light of Applicant’s cancellation of the claim.
5. Claims 108, 111, 114-120, 124, 126, and 129 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 an in vivo method of modifying a human CD14+ myeloid cell in a subject with modified mRNA, the method comprising the step of systemic delivery to said subject 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 recite a subject 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.
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
While independent Claim 108 has been amended to recite a subject 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.
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
While Claim 108 has been to recite systemic administration of the pharmaceutical composition comprising a lipid nanoparticle encapsulating the mRNA, those of ordinary skill in the art immediately recognize that “systemic delivery” is broader in scope than intravenous administration (Claim 115). As discussed above, the broader scope of “systemic delivery” is not supported by the priority documents, nor instant application.
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]).
At best, the specification discloses intravenous administration of the nucleic acid, e.g. [0373].
Claim 108 has been amended to recite a “human therapeutic polypeptide….is a chimeric antigen receptor”.
As a first matter, it is axiomatic that the chimeric antigen receptor is a therapeutic polypeptide. Instant specification fails to disclose a non-therapeutic CAR.
As a second matter, chimeric antigen receptors are not naturally-occurring polypeptides, nor naturally-occurring human polypeptides, and thus there is no such thing as a “human therapeutic polypeptide….is a chimeric antigen receptor”. Instant specification fails to disclose a human chimeric antigen receptor.
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 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 the broader genus of “systemic delivery”, Applicant should point out such support with particularity by page and line number in the reply to this Action.
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.
6. Claim 115 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 108 recites the step of systemic administration.
Claim 115, dependent upon Claim 108, recites the step of intravenous administration.
Claim 115 fails to further limit Claim 108 because Applicant’s priority documents and instant application fail to provide support for “systemic delivery” of the LNP encapsulating the mRNA. The only support is for intravenous delivery of the LNP encapsulating the mRNA, e.g. [0373].
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
To the extent Applicant argues otherwise, see above discussion in the Priority section and 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejection.
7. Claim 116 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
The claim has been amended to recite wherein the chimeric antigen receptor comprises:
i) an extracellular domain comprising an antigen binding domain [structure];
ii) a transmembrane domain operatively linked to the extracellular domain [structure]; and
iii) the CAR dimerizes or multimerizes with an endogenous receptor or transmembrane protein inside the myeloid cell [functional property(ies)].
Either (iii) functional language is an inherent property of (that naturally flows from) the chimeric antigen receptor of Claim 108, or it is not, and something of the of the chimeric antigen receptor of Claim 108 must change.
To the extent it is an inherent property of (that naturally flows from) the chimeric antigen receptor of Claim 108, then the instant claim fails to further limit the independent claim.
Therefore, the "wherein" clause is not considered to further limit the method defined by the claim and has not been given weight in construing the claims. See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171,26 USPQ2d 1018, 1023 (Fed Cir. 1993) ("A 'whereby' clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim."). See also Minton v. National Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003) ("A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.").
Those of ordinary skill in the art have long-recognized that chimeric antigen receptors naturally comprise:
i) an extracellular domain comprising an antigen binding domain; and
ii) a transmembrane domain operatively linked to the extracellular domain.
Those of ordinary skill in the art have long-recognized that chimeric antigen receptors also naturally comprise one or more intracellular signaling domains.
Instant specification fails to disclose chimeric antigen receptors devoid of one or more intracellular signaling domains.
Instant specification fails to disclose chimeric antigen receptors comprising:
i) an extracellular domain comprising an antigen binding domain; and
ii) a transmembrane domain operatively linked to the extracellular domain, but do not possess the functional property(ies) of:
iii) the CAR dimerizes or multimerizes with an endogenous receptor or transmembrane protein inside the myeloid cell.
'Even if such a phrase did hold patentable weight, the phrase would likely be rejected under 35 USC 112(b) for being indefinite because such a phrase would amount to a 'functional limitation' whereby one of ordinary skill in the art would essentially need to 'guess' what steps must occur in the claim, in addition to the positively-recited method steps, in order to result in 'wherein the....' (the 'intended result' phrase in the claim).
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
8. Claim(s) 116-120 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 claim has been amended to recite wherein the chimeric antigen receptor comprises:
i) an extracellular domain comprising an antigen binding domain [structure];
ii) a transmembrane domain operatively linked to the extracellular domain [structure]; and
iii) the CAR dimerizes or multimerizes with an endogenous receptor or transmembrane protein inside the myeloid cell [functional property(ies)].
Either (iii) functional language is an inherent property of (that naturally flows from) the chimeric antigen receptor of Claim 108, or it is not, and something of the of the chimeric antigen receptor of Claim 108 must change.
The claim denotes that not all of the chimeric antigen receptors of the independent Claim 108 and/or chimeric antigen receptors comprising:
i) an extracellular domain comprising an antigen binding domain;
ii) a transmembrane domain operatively linked to the extracellular domain (Claim 116),
are able to achieve the functional property(ies) of:
iii) the CAR dimerizes or multimerizes with an endogenous receptor or transmembrane protein inside the myeloid cell.
To the extent it is not an inherent property (that naturally flows) from the chimeric antigen receptor of the independent claim and/or Claim 116, then something must change. The claim is considered to lack adequate written description for failing to recite the structure(s) that is/are necessary and sufficient to predictably cause the recited functional language.
The limitation merely states a functional characteristic without providing any indication about how the functional characteristic is provided. The functional characteristic does not follow from (is not an inherent property of) the structure(s) recited in the claim(s), and the specification fails to disclose what structural changes to the chimeric antigen receptor is/are necessary and sufficient to predictably cause the recited functional language.
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).
A keyword search of the instant specification discloses only 1 result, in generic, boiler-plate form, to wit:
“the chimeric antigen receptor may dimerize or multimerize with a second receptor or transmembrane protein inside the myeloid cell, where the second receptor or transmembrane protein is an endogenous protein” (pg 85, [0455]).
There is no other description or disclosure for the structure/function nexus of the instantly recited functional language.
The claims fail to recite, and the specification fails to disclose, a first chimeric antigen receptor comprising:
i) an extracellular domain comprising an antigen binding domain; and
ii) a transmembrane domain operatively linked to the extracellular domain, but is unable to dimerize or multimerize with an endogenous receptor or transmembrane protein inside the myeloid cell, as opposed to
a second chimeric antigen receptor comprising:
i) an extracellular domain comprising an antigen binding domain; and
ii) a transmembrane domain operatively linked to the extracellular domain, that is necessarily and predictably able to dimerize or multimerize with an endogenous receptor or transmembrane protein inside the myeloid cell, for example.
The claims fail to recite, and the specification fails to disclose, a first chimeric antigen receptor comprising:
i) an extracellular domain comprising an antigen binding domain;
ii) a transmembrane domain operatively linked to the extracellular domain; and
iii) an intracellular signaling domain, but is unable to dimerize or multimerize with an endogenous receptor or transmembrane protein inside the myeloid cell, as opposed to
a second chimeric antigen receptor comprising:
i) an extracellular domain comprising an antigen binding domain;
ii) a transmembrane domain operatively linked to the extracellular domain; and
iii) an intracellular signaling domain, that is necessarily and predictably able to dimerize or multimerize with an endogenous receptor or transmembrane protein inside the myeloid cell, for example.
The claims fail to recite, and the specification fails to disclose, a first chimeric antigen receptor comprising:
i) an extracellular domain comprising an antigen binding domain;
ii) a transmembrane domain operatively linked to the extracellular domain; and
iii) at least two intracellular signaling domains, but is unable to dimerize or multimerize with an endogenous receptor or transmembrane protein inside the myeloid cell, as opposed to
a second chimeric antigen receptor comprising:
i) an extracellular domain comprising an antigen binding domain;
ii) a transmembrane domain operatively linked to the extracellular domain; and
iii) at least two intracellular signaling domains, that is necessarily and predictably able to dimerize or multimerize with an endogenous receptor or transmembrane protein inside the myeloid cell, for example.
The claims fail to recite, and the specification fails to disclose, how to transform or otherwise modify a first chimeric antigen receptor comprising:
i) an extracellular domain comprising an antigen binding domain;
ii) a transmembrane domain operatively linked to the extracellular domain; and
iii) at least one or two intracellular signaling domains, but is unable to dimerize or multimerize with an endogenous receptor or transmembrane protein inside the myeloid cell, as opposed to
a second chimeric antigen receptor comprising:
i) an extracellular domain comprising an antigen binding domain;
ii) a transmembrane domain operatively linked to the extracellular domain; and
iii) at least one or two intracellular signaling domains, that is necessarily and predictably able to dimerize or multimerize with an endogenous receptor or transmembrane protein inside the myeloid cell, for example.
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
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.
9. Claims 108, 111, 114-120, and 124 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
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 108 has been amended to recite the broad recitation “therapeutic polypeptide”, and the claim also recites “wherein…. human therapeutic polypeptide”, and “wherein the therapeutic polypeptide is a chimeric antigen receptor” which is/are the narrower statement(s) of the range/limitation.
Claim 118 has been amended to recite the broad recitation(s) “wherein the intracellular domain is an intracellular domain from a phagocytic receptor or a scavenger receptor”, and the claim also recites “wherein the intracellular domain from a phagocytic receptor or scavenger receptor is an intracellular domain from CD16a, …CD64, ….CD68, or… CD89”, which is/are the narrower statement(s) 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.
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.
Claim Rejections - 35 USC § 102
10. The prior rejection of Claims 108, 111, 115-118, 121, 125-126, and 129 under 35 U.S.C. 102(a)(1) as being anticipated by Yoon et al (Adoptive immunotherapy using human peripheral blood lymphocytes transferred with RNA encoding Her-2/neu-specific chimeric immune receptor in ovarian cancer xenograft model, Cancer Gene Therapy 16: 489-497, 2009), as evidenced by Google (CD14-negative myeloid cells, peripheral blood; last accessed July 29, 2025) and ThermoFisher mMESSAGE mMACHINE™ T7 ULTRA Transcription Kit (thermofisher.com/order/catalog/product/AM1345; last accessed July 29, 2025) is withdrawn in light of Applicant’s amendment to independent Claim 108 to recite an in vivo method, a limitation Yoon et al do not teach.
11. The prior rejection of Claims 108, 111, 115-116, 118-119, 121, 124-125, and 129 under 35 U.S.C. 102(a)(1) as being anticipated by Hung et al (Development of Anti-Human Mesothelin-Targeted Chimeric Antigen Receptor Messenger RNA–Transfected Peripheral Blood Lymphocytes for Ovarian Cancer Therapy, Human Gene Therapy 29(5): 614-625, available online May 1, 2018), as evidenced by Google (peripheral blood mononuclear cells; last accessed July 29, 2025) and ThermoFisher mMESSAGE mMACHINE™ T7 ULTRA Transcription Kit (thermofisher.com/order/catalog/product/AM1345; last accessed July 29, 2025) is withdrawn in light of Applicant’s amendment to independent Claim 108 to recite an in vivo method, a limitation Hung et al do not teach.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
12. The prior rejection of Claims 108, 111, 115-119, 121, 124-126, and 129 under AIA 35 U.S.C. 103 as being unpatentable over Yoon et al (2009; of record) in view of Hung et al (available online May 1, 2018; of record), Morrissey et al (Chimeric antigen receptors that trigger phagocytosis, eLife 7: e36688, 21 pages; doi.org/10.7554/eLife.36688; available online June 4, 2018; of record in IDS) and Herb et al (Highly Efficient Transfection of Primary Macrophages with In Vitro Transcribed mRNA, J. Vis. Exp. 153: e60143, 11 pages, doi:10.3791/60143; available online November 9, 2019) is withdrawn for reasons discussed above.
13. The prior rejection of Claim(s) 108 and 114 under AIA 35 U.S.C. 103 as being unpatentable over Yoon et al (2009; of record) in view of Hung et al (available online May 1, 2018; of record), Morrissey et al (available online June 4, 2018; of record in IDS) and Herb et al (available online November 9, 2019; of record), as applied to Claims 108, 111, 115-119, 121, 124-126, and 129 above, and in further view of Kariko et al (Generating the optimal mRNA for therapy: HPLC purification eliminates immune activation and improves translation of nucleoside-modified, protein-encoding mRNA, Nucleic Acids Research 39(21): e142, 10 pages, doi:10.1093/nar/gkr695; available online September 2, 2011) is withdrawn for reasons discussed above.
14. The prior rejection of Claim(s) 118-120 under AIA 35 U.S.C. 103 as being unpatentable over Yoon et al (2009; of record) in view of Hung et al (available online May 1, 2018; of record), Morrissey et al (available online June 4, 2018; of record in IDS) and Herb et al (available online November 9, 2019; of record), as applied to Claims 108, 111, 115-119, 121, 124-126, and 129 above, and in further view of Smith et al (U.S. 2014/0134142), Juillerat et al (U.S. 2017/0073423), and Oda et al (U.S. 2018/0044404) is withdrawn for reasons discussed above.
15. Claims 108, 111, 115-117, 119, and 124 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Kauffman et al (Efficacy and immunogenicity of unmodified and pseudouridine modified mRNA delivered systemically with lipid nanoparticles in vivo, Biomaterials 109: 78-87, 2016) 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), Jabulowsky et al (1238TiP - A first-in-human phase I/II clinical trial assessing novel mRNA-lipoplex nanoparticles encoding shared tumor antigens for immunotherapy of malignant melanoma, Annals of Oncology 29(Supplement 8): Abstract only, pg viii439, October 2018), and Morrissey et al (available online June 4, 2018; of record in IDS).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Instant Claim 108 is unnecessarily verbose.
Thus, recitation “wherein the mRNA encapsulated in the LNP is taken up by a myeloid cell in vivo” is unnecessary and internally redundant.
It is axiomatic natural law of cell biology that the human CD14+ myeloid cell must necessarily take up the LNP in order to become engineered, per the preamble.
It is axiomatic that the chimeric antigen receptor is a therapeutic polypeptide. Instant specification fails to disclose a non-therapeutic CAR. Chimeric antigen receptors are not naturally-occurring human polypeptides, and thus there is no such thing as a “human therapeutic polypeptide….is a chimeric antigen receptor”. Instant specification fails to disclose a naturally-occurring human chimeric antigen receptor. To the extent Applicant argues otherwise, then see above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph and 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejections.
Thus, recitations “a human therapeutic polypeptide”, “therapeutic polypeptide”, and “wherein the therapeutic polypeptide” are unnecessary and internally redundant.
Claim 108 can instead be drafted more concisely, to wit:
An in vivo method of producing an engineered human CD14+ myeloid cell in a subject, the method comprising the step of administering by intravenous injection to said subject a pharmaceutical composition comprising a lipid nanoparticle (LNP) encapsulating a mRNA encoding a chimeric antigen receptor (CAR), thereby producing an engineered human CD14+ myeloid cell.
With respect to Claim 108, Kauffman et al is considered relevant prior art for having taught an in vivo method of producing engineered CD14+ myeloid cells, the method comprising the step of administering to a mouse subject by intravenous injection (e.g. pg 81, col. 1, “intravenous administration”) a pharmaceutical composition comprising lipid nanoparticles encapsulating mRNA (e.g. pg 79, col. 1, Results, 2.1 mRNA synthesis and LNP formulation) encoding the artisan’s protein of interest.
Kauffman et al taught that it is natural law of biology that the LNPs are taken up by phagocytic myeloid cells, including CD14+ myeloid cells, in the bloodstream (e.g. pg 84, col. 1; Figure 7), whereby those of ordinary skill in the art have long-recognized that it is natural law of cell biology that phagocytic macrophages, dendritic cells, and monocytes are CD14+ myeloid cells (Google).
Kauffman et al do not teach wherein the mRNA encodes a chimeric antigen receptor.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim 108, Yoon et al is considered relevant prior art for having taught an ex vivo method of modifying human immune cells, to wit, human peripheral blood lymphocytes, the method comprising the step of delivering to said human immune cells an mRNA encoding a chimeric antigen receptor (e.g. Title; Abstract; pg 490, col. 2, Methods).
Similarly, Hung et al is considered relevant prior art for having taught an ex vivo method of modifying an immune cell, to wit, peripheral blood lymphocytes, the method comprising the step of delivering to said immune cells an mRNA encoding a chimeric antigen receptor (e.g. Title; pg 616, col. 2, Methods, mRNA synthesis).
Neither Yoon et al nor Hung et al teach ipsis verbis that the human peripheral blood cells comprise CD14+ myeloid cells. However, Google evidences that peripheral blood lymphocytes inherently and naturally comprise CD14-positive myeloid cells, e.g. monocytes and macrophages.
Neither Kauffman et al, Yoon et al, nor Hung et al teach wherein the subject is a human subject.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim 108, Jabulowsky et al is considered relevant prior art for having taught an in vivo method of producing engineered human CD14+ myeloid cells, the method comprising the step of administering to a human subject by intravenous injection a pharmaceutical composition comprising lipid nanoparticles encapsulating mRNA encoding the artisan’s protein of interest.
Morrissey et al is considered relevant prior art for having taught a modified immune cell, to wit, macrophages, expressing a chimeric antigen receptor (e.g. Abstract). Morrissey et al taught that macrophages are art-recognized critical effectors of the innate immune system, and harnessing macrophages to combat tumor growth is of longstanding interest because macrophages are uniquely capable of penetrating solid tumors, while other immune cells like T cells, are physically excluded or inactivated (e.g. pg 1, Introduction).
Resolving the level of ordinary skill in the pertinent art.
People of the ordinary skill in the art will be highly educated individuals such as medical doctors, scientists, or engineers possessing advanced degrees, including M.D.'s and Ph.D.'s. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in molecular biology, immunology, and chimeric antigen receptors. Therefore, the level of ordinary skill in this art is high.
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at ___, 82 USPQ2d at 1396.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute a first protein of interest encoded by an mRNA, as taught by Kauffman et al, with a second protein of interest encoded by an mRNA, to wit, a chimeric antigen receptor, as taught by Yoon et al, Hung et al, and Morrissy et al, in an in vivo method of modifying a CD14+ myeloid cell to express a chimeric antigen receptor with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. Those of ordinary skill in the art have long-recognized the scientific and technical concepts of synthesizing mRNAs encoding the artisan’s protein of interest, whereby said protein encoding by the mRNA is irrelevant to the lipid nanoparticle encapsulating the mRNA.
Prior to the effective filing date of the instantly claimed invention, it also would have been obvious to one of ordinary skill in the art to substitute a first mammalian subject, e.g. a mouse, as taught by Kauffman et al, with a second mammalian subject, to wit, a human, in an in vivo method of engineering a CD14+ myeloid cell comprising the step of administering by intravenous administration to said target mammal lipid nanoparticles encapsulating mRNA encoding the artisan’s protein of interest, including a chimeric antigen receptor, with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute a substitute a first mammalian subject, e.g. a mouse, with a second mammalian subject, to wit, a human, in an in vivo method of engineering a CD14+ myeloid cell comprising the step of administering by intravenous administration to said target mammal lipid nanoparticles encapsulating mRNA encoding the artisan’s protein of interest, including a chimeric antigen receptor because those of ordinary skill in the art previously recognized the scientific and technical concepts that:
i) the mouse system has long-been used in the art as a model system for human disease;
ii) Kauffman et al taught that the method of intravenously administering LNPs encapsulating mRNA has clinical (syn. human subjects) potential (e.g. pg 83, col. 1);
iii) chimeric antigen receptors have long-been recognized for their utility to treat human subjects suffering from cancer (Yoon et al, Hung et al, Morrissy et al);
iv) Morrissey et al taught that CAR-expressing macrophages direct said macrophages to engulf the specific targets recognized by the CAR, including cancer cells (e.g. Abstract), and that harnessing macrophages to combat tumor growth has been a longstanding interest, as they are uniquely capable of penetrating solid tumors, while other immune cells, like T cells, are physically excluded or inactivated (e.g. pg 1, last para); and
v) Jabulowsky et al successfully demonstrated an in vivo method of producing engineered human myeloid cells, the method comprising the step of administering to a human subject by intravenous injection a pharmaceutical composition comprising lipid nanoparticles encapsulating mRNA encoding the artisan’s protein of interest.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claim 111, Kauffman et al taught wherein the mRNA is modified to comprise a 5’ cap (e.g. pg 79, col. 1, Results, 2.1 mRNA synthesis and LNP formulation, “5’-capped”).
Yoon et al do not teach ipsis verbis wherein the mRNA is a modified mRNA. However, Yoon et al used the mMESSAGE mMACHINE™ T7 ULTRA Transcription Kit (pg 490, col. 2, Methods, in vitro transcription of mRNA), and the ThermoFisher product teaches that the mRNA is modified to comprise an artificial 5’ cap, e.g. ARCA 5’ cap.
Hung et al do not teach ipsis verbis wherein the mRNA is a modified mRNA. However, Hung et al used the mMESSAGE mMACHINE™ T7 ULTRA Transcription Kit pg 616, col. 2, Methods, mRNA synthesis), and the ThermoFisher product teaches that the mRNA is modified to comprise an artificial 5’ cap, e.g. ARCA 5’ cap.
With respect to Claim 115, Kauffman et al is considered relevant prior art for having taught intravenous administration (e.g. pg 81, col. 1, “intravenous administration”) to a mouse subject of a pharmaceutical composition comprising lipid nanoparticles encapsulating mRNA (e.g. pg 79, col. 1, Results, 2.1 mRNA synthesis and LNP formulation) encoding the artisan’s protein of interest.
With respect to Claim 116, Yoon et al taught wherein the CAR comprises an extracellular antigen-binding domain, a CD28 intracellular signaling domain and a CD3zeta intracellular signaling domain (e.g. pg 490, col. 2, Methods, in vitro transcription of mRNA), whereby those of ordinary skill in the art would immediately recognize that the CAR must necessarily comprise a transmembrane domain, thereby linking the extracellular antigen-binding domain to the intracellular signaling domains.
Hung et al taught wherein the CAR comprises an extracellular antigen-binding domain, a transmembrane domain, a 4-1BB intracellular signaling domain, and a CD3zeta intracellular signaling domain (e.g. Figure 1).
Morrissy et al taught wherein the CAR comprises an extracellular antigen-binding domain, a transmembrane domain, and a FcgammaR, CD3zeta, or CD19 intracellular signaling domain (e.g. Figures 1, 3, 4).
The presence of the CD28 intracellular signaling domain and a CD3zeta intracellular signaling domain (Yoon et al), the 4-1BB intracellular signaling domain and a CD3zeta intracellular signaling domain (Hung et al), and/or the FcgammaR, CD3zeta, or CD19 intracellular signaling domain (Morrissy et al) is/are considered to confer the ability to dimerize or multimerize with an endogenous receptor or transmembrane protein inside the myeloid cell, absent objective evidence to the contrary.
To the extent Applicant argues otherwise, then see above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph rejection.
With respect to Claim 117, Yoon et al taught wherein the extracellular antigen-binding domain is a HER2-binding domain, to wit, an scFv that specifically binds to HER2 (e.g. Title; pg 490, col. 2, Methods, in vitro transcription of mRNA).
With respect to Claim 119, Hung et al taught wherein the CAR comprises a CD8 hinge and CD8 transmembrane domain (e.g. Figure 1; pg 616, col. 1, Methods, Gene constructs).
Morrissey et al taught wherein the CAR comprises a CD8 hinge and CD8 transmembrane domain (e.g. pg 9, Materials and Methods, CD19-mMegf10 CAR, CD8 stalk (syn. hinge)/transmembrane).
With respect to Claim 124, neither Kauffman et al, Yoon et al, nor Hung et al teach ipsis verbis that the peripheral blood immune cells are CD14+ and CD16-. However, Google evidences that peripheral blood lymphocytes inherently and naturally comprise CD14+ and CD16- monocytes, as they are the “classical” and most abundant monocyte population.
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
16. Claims 108, 111, and 114 are rejected 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).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Neither Yoon et al, Hung et al, nor Morrissey et al teach wherein the mRNA is purified using HPLC.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claims 108 and 114, Kauffman et al taught that those of ordinary skill in the art have used HPLC to purify their mRNA (e.g. Table 1, “mRNA HPLC-purified”).
Similarly, Kariko et al is considered relevant prior art for having taught a method of modifying an immune cell, e.g. dendritic cells (pg 2, col. 1, Methods, Cells), the method comprising the step of purifying modified mRNA using HPLC (e.g. pg 2, col. 1, mRNA synthesis, HPLC purification of RNA).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to modify a method of modifying an immune cell with a mRNA to comprise the step of purifying the mRNA using HPLC with a reasonable expectation of success because Kauffman et al taught that such was an art-recognized technique previously successfully reduced to practice (e.g. Table 1, “mRNA HPLC-purified”) and Kariko et al successfully demonstrated the ability to purify in vitro synthesized mRNA using HPLC prior to introducing the thus-purified mRNA into target cells, including target immune cells. Kariko et al taught that contaminants of in vitro transcribed RNA are responsible for innate immune activation, and their removal by HPLC results in purified mRNA that does not induce interferons and inflammatory cytokines, and results in 10- to 1000-fold greater yields of transfected primary cells (e.g. Abstract).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claim 111, Kauffman et al taught wherein the mRNA is modified to comprise a 5’ cap (e.g. pg 79, col. 1, Results, 2.1 mRNA synthesis and LNP formulation, “5’-capped”).
Yoon et al do not teach ipsis verbis wherein the mRNA is a modified mRNA. However, Yoon et al used the mMESSAGE mMACHINE™ T7 ULTRA Transcription Kit (pg 490, col. 2, Methods, in vitro transcription of mRNA), and the ThermoFisher product teaches that the mRNA is modified to comprise an artificial 5’ cap, e.g. ARCA 5’ cap.
Hung et al do not teach ipsis verbis wherein the mRNA is a modified mRNA. However, Hung et al used the mMESSAGE mMACHINE™ T7 ULTRA Transcription Kit pg 616, col. 2, Methods, mRNA synthesis), and the ThermoFisher product teaches that the mRNA is modified to comprise an artificial 5’ cap, e.g. ARCA 5’ cap.
Kariko et al taught the modified mRNA comprises a 5’ cap and/or pseudouridine (e.g. pg 2, col. 1, Methods, mRNA synthesis).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
17. Claims 118-120 are rejected 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).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Instant Claim 118 is unnecessarily verbose.
Claim 118 can instead be drafted more concisely, to wit:
The method of claim 116, wherein the CAR further comprises a CD16a, CD64, CD68, or CD89 intracellular domain.
To the extent Applicant argues otherwise, then see above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejection.
Yoon et al taught wherein the CAR further comprises a CD3zeta intracellular signaling domain (e.g. pg 490, col. 2, Methods, in vitro transcription of mRNA).
Hung et al taught wherein the CAR further comprises a CD3zeta intracellular signaling domain (e.g. Figure 1).
Morrissey et al taught wherein the CAR further comprises a CD3zeta intracellular signaling domain (e.g. pg 5, para 3; Figure 3b) or a PI3K recruitment domain (e.g. Abstract), thereby increasing cancer cell engulfment.
Neither Yoon et al, Hung et al, nor Morrissey et al, teach wherein the CAR comprises a FcRalpha (syn. CD89) transmembrane domain and/or an intracellular FcRalpha (syn. CD89) signaling domain.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claims 118-120, Smith et al is considered relevant prior art for having disclosed chimeric antigen receptors comprising an extracellular antigen-binding domain specific for HER2 (e.g. [0076]), wherein the antigen-binding domain is an scFv (e.g. [0078]), a CD8 hinge domain (e.g. Example 6, [0350]), a FcRalpha (syn. CD89) transmembrane domain (e.g. [0031], CD8 stalk domain fused to FcRalpha transmembrane domain), and a FcRalpha (syn. CD89) intracellular signaling domain (e.g. Example 6, [0350]; Figure 4b-c).
Juillerat et al is considered relevant prior art for having disclosed chimeric antigen receptors comprising an extracellular antigen-binding domain specific for HER2 (e.g. [0067, 69]), wherein the antigen-binding domain is an scFv (e.g. [0065]), a CD8 hinge domain (e.g. [0085]), a CD8 or FcRalpha (syn. CD89) transmembrane domain (e.g. [0086], and a FcRalpha (syn. CD89) intracellular signaling domain (e.g. [0123-124]; claim 14).
Oda et al is considered relevant prior art for having disclosed chimeric antigen receptors comprising an extracellular antigen-binding domain, wherein the antigen-binding domain is an scFv (e.g. [0053, 113]), a CD8 transmembrane domain (e.g. [0137]) or FcRalpha (syn. CD89) transmembrane domain (e.g. [0086, 137], claim 23), and a FcRalpha (syn. CD89) intracellular signaling domain (e.g. [0057, 129]; claim 28).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute a first transmembrane domain, e.g. a CD8 transmembrane domain, and/or a first intracellular signaling domain, with a second transmembrane domain, e.g. a CD89 (syn. FcRalpha) transmembrane domain, and/or a second intracellular signaling domain, e.g. a CD89 (syn. FcRalpha), in a chimeric antigen receptor with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute a first transmembrane domain, e.g. a CD8 transmembrane domain, and/or a first intracellular signaling domain, with a second transmembrane domain, e.g. a CD89 (syn. FcRalpha) transmembrane domain, and/or a second intracellular signaling domain, e.g. a CD89 (syn. FcRalpha), in a chimeric antigen receptor because those of ordinary skill in the art previously recognized the scientific and technical concepts that chimeric antigen receptors, including HER2-CARs, may comprise a FcRalpha (syn. CD89) transmembrane domain and a FcRalpha (syn. CD89) intracellular signaling domain (Smith et al, Juillerat et al, Oda et al), whereby said FcRalpha (syn. CD89) transmembrane domain is substitutable with a CD8 transmembrane domain (e.g. Juillerat et al, Oda et al) and said FcRalpha (syn. CD89) intracellular domain is substitutable with other art-recognized CAR intracellular signaling domains (e.g. Oda et al), and whereby the prior art successfully reduced to practice a CAR comprising a CD8 hinge domain, a FcRalpha transmembrane domain, and a FcRalpha intracellular domain (e.g. Smith et al, Example 6; Juillerat et al [0123-124]).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Double Patenting
18. The prior rejection of Claims 108, 111, 114-121, 124-126, and 129 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 7, 9-10, and 12 of U.S. Patent 10,980,836 in view of Yoon et al (2009; of record), Hung et al (available online May 1, 2018; of record), Morrissey et al (available online June 4, 2018; of record in IDS), Herb et al (available online November 9, 2019; of record), Kariko et al (available online September 2, 2011; of record), 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 amendments to instant independent Claim 108 to recite an in vivo method of engineering the CD14+ human myeloid cell, a limitation not claimed by ‘836 (in vitro or ex vivo).
19. The prior rejection of Claims 108, 111, 114-121, 124-126, and 129 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-5, 7-10 and 12-13 of U.S. Patent 11,013,764 in view of Yoon et al (2009; of record), Hung et al (available online May 1, 2018; of record), Morrissey et al (available online June 4, 2018; of record in IDS), Herb et al (available online November 9, 2019; of record), Kariko et al (available online September 2, 2011; of record), 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 amendments to instant independent Claim 108 to recite an in vivo method of engineering the CD14+ human myeloid cell, a limitation not claimed by ‘764 (in vitro or ex vivo).
20. The prior rejection of Claims 108, 111, 114-121, 124-126, and 129 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-4 and 9-16 of U.S. Patent 11,026,973 in view of Yoon et al (2009; of record), Hung et al (available online May 1, 2018; of record), Morrissey et al (available online June 4, 2018; of record in IDS), Herb et al (available online November 9, 2019; of record), Kariko et al (available online September 2, 2011; of record), 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 amendments to instant independent Claim 108 to recite an in vivo method of engineering the CD14+ human myeloid cell, a limitation not claimed by ‘973 (in vitro or ex vivo).
Conclusion
21. No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638