DETAILED ACTION
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 .
Status of the Claims
Claims 1, 4, 6, 8-10, 12, 14-17, 32, 45, 58, 64, 66-69, 72, 75-76, 78, and 92 are pending.
Applicant’s election without traverse of Group I, claims 1, 4, 6, 8-10, 12, and 14-16 in the reply filed on 11/12/2025 is acknowledged.
Claims 17, 32, 45, 58, 64, 66-69, 72, 75-76, 78, and 92 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/25/2025.
Claims 1, 4, 6, 8-10, 12, 14-16 are examined.
Claim Rejections - 35 USC § 112
35 U.S.C. 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 6, 8-10, 12, 14-16 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 is indefinite because it is not clear if the claim encompasses a cell comprising a Rac gene that has increased expression resulting in a cell with an enhanced Rac activity/property, or if the claim is limited to only a cell comprising a Rac gene encoding a Rac protein with an activating mutation.
Claim 1 includes the term “a genetically engineered activated phagocytic cell comprising an activated Rac gene encoding an activated Rac protein…”. Regarding the activated phagocytic cell, the specification recites that “[Phagocytic cells of the disclosure] are capable of expressing an activated Rac protein and/or a Rac protein at activating expression level.” (Spec. [0102]).
The specification defines “activated Rac gene” as a Rac gene encoding an activated Rac protein. (Spec. [0104]). According to the specification, an “activated Rac protein” refers to a Rac protein having a sequence resulting in and/or that provides an enhanced Rac property. (Spec. [0103]). But the specification also states that the term “activated” “or “activating” as used herein with reference to an expression level of a Rac protein indicates an expression level that is increased relative to a baseline expression level, and the increased expression level results in enhanced Rac properties. (Spec. [0104]). A Rac gene/Rac protein with an increased expression level is by definition also an activated Rac gene/protein according to the specification.
Regarding the term “enhanced Rac properties”, the specification recites that “enhanced Rac properties” …have been shown to enhance phagocytosis of the activated phagocyte to the extent of enabling engulfment and/or trogocytosis on living cells. (Spec. [0007]). Then in another section Enhanced Rac properties …are increased Rac properties determined with respect to Rac properties of a non-activated Rac protein having SEQ ID NO: 1. (Spec. [0108]). Then in another section, enhanced Rac properties result from an increased expression level of Rac. (Spec. [0105]).
So, there appear to be two competing definitions of what an activated Rac gene is. Namely is an activated Rac gene: (1) a Rac gene that has a particular sequence or activating mutation that encodes an “activated” Rac gene with “enhanced properties”, (2) any Rac gene with increased expression relative to baseline, resulting in “enhanced properties”, or (3) some combination of options 1 and 2.
Similarly, there are two competing definitions of what an “activated Rac protein” is. Is a Rac protein (1) A rac protein with a particular sequence that gives it enhanced properties, (2) any Rac protein that has an increased expression level that results in “enhanced properties”, or (3) some combination of options 1 and 2?
Since it isn’t clear what the metes and bounds of the claim are, the claim must be considered indefinite.
So, for purposes of examination, the BRI of a “a phagocytic cell…comprising an activated Rac gene encoding an activated Rac protein…” will include any phagocyte that has that has any level of increased expression of any Rac gene, OR any phagocyte that encodes any Rac protein that enhances the engulfment and/or trogocytosis activity of the phagocyte.
Claims 1, 6, 8-10, 12, 14-16 are rejected for being dependent on an indefinite claim. The limitations of claim 4 resolve the indefiniteness issue.
35 U.S.C. 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 6, 8-10, 12, 14-16 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.
Included in a potential interpretation for claim 1 is any phagocyte encoding a Rac protein that would result in a Rac protein with “enhanced properties”, i.e., a Rac with an activating mutation. The specification recites that such a sequence results in and/or that provides an enhanced Rac property, (Spec. [0105]), or that the Rac gene may have mutations enhancing a Rac property and/or activity. (Spec. [0133]). The specification provides many examples of mutations that could qualify as resulting in a Rac with enhanced properties. (Spec. 0160-168, 204, Example 4). The specification also provides examples of how to detect enhanced properties of candidate Rac proteins (Spec. Example 5, 6). However, the specification does not reasonably describe every conceivable mutation known or yet to be discovered that could result in an enhanced property.
Claims 6, 8-10, 12, and 14-16 are rejected for being dependent on claim 1. The limitations of claim 4 resolve the written description issue.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Hsu, Pulgar, and Ladd
Hsu AP et al., Dominant activating RAC2 mutation with lymphopenia, immunodeficiency , and cytoskeletal defects. Blood. 2019 May 2;133(18):1977-1988 ( Provided in IDS of 8/1/2023)
Teresa Gómez del Pulgar ; Juan Carlos Lacal RAC2 (ras-related C3 botulinum toxin substrate 2 (rho family, small GTP binding protein Rac2)) Atlas Genet Cytogenet Oncol Haematol. 2008-08-01
Ladd, Paula D., Jill Sergesketter Butler, and David G. Skalnik. "Identification of a genomic fragment that directs hematopoietic-specific expression of Rac2 and analysis of the DNA methylation profile of the gene locus." Gene 341 (2004): 323-333.
Claims 1, 4, 6, and 8 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more.
Regarding claim 1, the claim encompasses effectively any cell with phagocytic activity that comprises an activated Rac gene encoding an activated Rac protein that is under the control of a promoter and a regulatory region that drives expression of said activated Rac gene.
Regarding the “genetically engineered activated phagocytic cell comprising” limitation of the preamble, the term “genetically engineered” is not limiting because the body of the claim describes a complete invention and the language recited solely in the preamble does not provide any distinct definition of any of the claimed invention' s limitations, namely that the cell must comprise an activated Rac gene and protein under the control of a promoter and regulatory region allowing expression in the activated phagocytic cell. A suggested remedy to this would be to include in the claim body a limitation that requires that the claimed activated Rac and/or regulatory sequences be engineered/transduced, etc. into the cell. Thus, the preamble of the claim as written is not considered a limitation and is of no significance to claim construction. See Pitney Bowes, Inc. v. Hewlett-Packard Co., 182 F.3d 1298, 1305, 51 USPQ2d 1161, 1165 (Fed. Cir. 1999). See MPEP § 2111.02.
Hsu teaches that a naturally occuring cell comprises an activated Rac gene encoding an activated Rac protein. Hsu identified 3 patients with de novo RAC2[E62K] mutations resulting in severe T- and B-cell lymphopenia, myeloid dysfunction, and recurrent respiratory infections. The specification recites that a Rac activating mutation can comprise an E62K mutation. (Specification [0164]).
Hsu teaches that lymphocytes expressing Rac2[E62K] mutations were known to be naturally-occuring. Hsu teaches that RAC2 is expressed primarily in hematopoietic cell lineages. (Hsu, Introduction). Hsu found that neutrophils from RAC2[E62K] patients exhibited excessive superoxide production, impaired fMLF-directed chemotaxis, and abnormal macropinocytosis. (Hsu, Abstract).
Hsu does not specify what if any promoter that a naturally-occuring Rac2 is under the control of, but it does stand to reason that Hsu teaches that there must be at least one promoter and regulatory region driving Rac2’s expression since it is being expressed in the lymphocytes of Hsu’s subjects, and thus causing their diseases.
Regarding the promoter and regulatory region limitations, Pulgar and Ladd teach that naturally-occuring Rac2 is under the control of at least one phagocyte promoter and a first additional phagocyte regulatory region in a configuration allowing expression of the naturally-occuring Rac gene in the activated phagocytic cell. Pulgar teaches that The Rac2 gene sequence contains 7 exons and is expressed specifically in hematopoietic cells. (Pulgar, DNA/RNA section). The human Rac2 gene promoter lacks TATA and CCAAT boxes, utilizes multiple transcription initiation sites, and contains several putative Sp1 binding sites, which is common in promoters that lack TATA boxes (Ladd et al., 2004). (Pulgar, DNA/RNA section, referencing (Ladd). The specification defines “phagocyte promoter” as “a nucleotide sequence that drives or regulates expression in phagocytes.” (Spec. [0170]). Thus, Rac2 has several promoters by this definition as it is known to utilize multiple transcription initiation sites and Sp1 binding sites.
This judicial exception is not integrated into a practical application because no practical application is claimed, only the product itself is claimed. The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because there are no additional elements claimed.
Thus, the cell of claim 1 is drawn to a product of nature without significantly more.
Regarding claim 4, Hsu teaches that lymphocytes expressing Rac2[E62K] mutations were known to be naturally-occuring. Hsu teaches that RAC2 is expressed primarily in hematopoietic cell lineages. (Hsu, Introduction).
Regarding claim 6, promoters are generally classified as either constitutive (always "on") or conditional (regulated/inducible/repressible). Thus, though Pulgar and Ladd don’t appear to specify which type of promoter that exists in nature for Rac2, they still teach that naturally-occuring Rac2 is under the control of at least one phagocyte promoter that must be either constitutive or conditional.
Regarding claim 8, Pulgar and Ladd teach that naturally-occuring Rac2 is under the control of at least one phagocyte promoter and a first additional phagocyte regulatory region in a configuration allowing expression of the activated Rac gene in the activated phagocytic cell. Pulgar teaches that The Rac2 gene sequence contains 7 exons and is expressed specifically in hematopoietic cells. (Pulgar, DNA/RNA section). The human Rac2 gene promoter lacks TATA and CCAAT boxes, utilizes multiple transcription initiation sites, and contains several putative Sp1 binding sites, which is common in promoters that lack TATA boxes (Ladd et al., 2004). (Pulgar, DNA/RNA section, referencing (Ladd). Thus, the claimed gene expression cassette for Rac2 is naturally occuring.
Claim Rejections - 35 USC § 102
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 (i.e., changing from AIA to pre-AIA ) 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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim interpretation (see 35 USC § 101 and 35 USC § 112(b) rejections)
Regarding the “genetically engineered activated phagocytic cell comprising” limitation of the preamble, the term “genetically engineered” is not limiting because the body of the claim describes a complete invention and the language recited solely in the preamble does not provide any distinct definition of any of the claimed invention' s limitations.
For purposes of examination, the BRI of a “a phagocytic cell…comprising an activated Rac gene encoding an activated Rac protein…” encompasses any phagocyte that has any level of naturally increased expression of any Rac gene in response to a natural stimulus. In other words, this limitation reads on essentially any phagocytic cell.
The specification defines “activated Rac gene” as a Rac gene encoding an activated Rac protein. (Spec. [0104]). According to the specification, an “activated Rac protein” refers to a Rac protein having a sequence resulting in and/or that provides an enhanced Rac property. (Spec. [0103]). But the specification also states that the term “activated” “or “activating” as used herein with reference to an expression level of a Rac protein indicates an expression level that is increased relative to a baseline expression level, and the increased expression level results in enhanced Rac properties. (Spec. [0104]). A Rac gene/Rac protein with an increased expression level is by definition also an activated Rac gene/protein according to the invention.
Gu
Claims 1, 6, 8-10, 12, and 14-16 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by:
Gu X, He D, Li C, Wang H, Yang G. Development of Inducible CD19-CAR T Cells with a Tet-On System for Controlled Activity and Enhanced Clinical Safety. Int J Mol Sci. 2018 Nov 3;19(11):3455
As evidenced by:
Pulgar et al., ; RAC2 (ras-related C3 botulinum toxin substrate 2 (rho family, small GTP binding protein Rac2)) Atlas Genet Cytogenet Oncol Haematol.2008-08-01
Ladd, Paula D., Jill Sergesketter Butler, and David G. Skalnik. "Identification of a genomic fragment that directs hematopoietic-specific expression of Rac2 and analysis of the DNA methylation profile of the gene locus." Gene 341 (2004): 323-333.
Guo, Fukun, et al. "Rac GTPase isoforms Rac1 and Rac2 play a redundant and crucial role in T-cell development." Blood, The Journal of the American Society of Hematology 112.5 (2008): 1767-1775, and
Cernuda-Morollón et al., Rac activation by the T-cell receptor inhibits T cell migration. PLoS One. 2010 Aug 25;5(8):e12393
Regarding claims 1, 6, 8-10, 12, and 14-16, Gu teaches a CAR-T cell, where expression of the CAR is under the control of an inducible Tet-On System, which is a system comprising two promoters. The TET-on system consists of a constitutively on promoter (a second phagocyte promoter) which expresses a transcription factor that in the presence of doxycycline binds to the TRE promoter, which induces the expression of Gu’s CAR. So, Gu teaches the cell of claim 1, wherein the claimed cell comprises a CAR gene under the control of a second phagocyte promoter (where the second phagocyte promoter may be considered to be either the constitutive CMV promoter or the dox-reactivew transcription factor dependent conditional promoter of the TET system). (Gu, Abstract, Introduction, section 2.4).
Regarding the activated Rac gene limitation, there is reason to believe that Gu’s T cells naturally comprise an activated Rac gene encoding an activated Rac protein. As discussed in MPEP § 2112, citing In re Best (195 USPQ 430) and In re Fitzgerald (205 USPQ 594), the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph). In the instant case, there is reason to believe that Gu’s T cells comprise an activated Rac gene encoding an activated Rac protein, since T cells are known to naturally express Rac 1 and Rac2 (Guo, Title, Abstract, see also Pulgar and Ladd), and it is also known in the art that a T cell increases expression of Rac genes in response to natural stimuli (TCR activation). (Cernuda-Morollon, Abstract)).
Conclusion
Claims 1, 4, 6, 8-10, 12, 14-16 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to THOMAS RUSSE AMICK whose telephone number is (571)272-5474. The examiner can normally be reached 7:30-5 M-F.
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/THOMAS R. AMICK/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638