DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s election of group I, drawn to a modified CXCR3+ T cell expressing a CXCR3 transgene, in the reply filed on 6/16/26 is acknowledged. Applicant has further claimed CXCR3alt/SEQ ID NO: 6 as the species of CXCR3, a CAR as the species of modification, and CD8+ memory T cells as the species of immune cells. Applicant has amended claims 1-14 and 20, such that they are now directed to a method of treating cancer in a subject comprising administering to the subject a modified CSCR3 expressing T cell. This is distinct from the elected group of a modified CXCR3+ T cell, and only claim 17, as well as linking claims 15-16 and 19 are now part of elected group I. Newly amended claims 1-14 and 20 are directed to an invention that is independent or distinct from the elected invention for the following reasons:
Groups 1 and 2 are directed to products, and claims 1-14 and 20 are directed to methods of using the products. Therefore, Claims 1-14 and 20 corresponded to group 3, a method of treating cancer in a subject comprising administering to the subject a modified CSCR3 expressing T cell.
Groups 1-3 do not relate to a single general inventive concept under PCT Rule 13.1 because, under PCT Rule 13.2, they lack the same or corresponding special tech-nical features for the following reasons:
The groups lack unity of invention because even though the inventions of these groups require the technical feature of an immune cell expressing a CXCR3 variant, this technical feature is not a special technical feature as it does not make a con-tribution over the prior art in view of WO 98/11218, which discloses CD3+ T cells expressing a CXCR3A transgene.
Accordingly, claims 1-14, 18, and 20 (corresponding to non-elected groups 2-3) are withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b).
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Claims 15-17 and 19 are being acted upon.
Claim 17 is objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim cannot reference two sets of claims to different features. In the instant case the claim references the method of claim 1, but also the product of claim 15. See MPEP § 608.01(n). Nevertheless, in the interest of compact prosecution, the claim is being treated as being directed to the isolated cells according to claim 15, comprising at least 50% of modified CD3+ T cells, wherein the modified CD3+ T cells express a CXCR3 transgene encoding the human CXCR3 variant.
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 15-17 and 19 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.
Regarding claims 15-17 and 19, the phrase "particularly" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). For example, the claims recite a preparation of immune cells, “particularly” a preparation of T cells. This represents a broad limitation and narrow limitation in the same claim (immune cells or T cells) which is indefinite. The same is true for the other “particular” limitations of claims 15-17 and 19 (for example in claim 15, 17 and 19, the claim recites at least 50%, particularly at least 70%, i.e. a broad range and a narrow range in the same claim). See also claim 16, which recites a cancer patient sample, particularly a peripheral blood sample. 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).. 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.
Claim 15 is indefinite in that it recites two different limitations with different scopes, rendering the claims unclear. The claim recites that the cells express “one or more human CXCR3 variants selected from CXCR3A, CXCR3alt+, and/or CXCR3B”, and the claim also recites a limitation “wherein the human CXCR3 variant, or one of the human CXCR3 variants is CXCR3A and/or CXCR3 alt”. For example, in the first limitation, one could select CXCR3B as the human CXCR variant, but then the claim seems to actually require that the variant is selected from CXCR3A or CXCR3alt. Thus, the claim scope is unclear. Does the claim intend that the cells express one or more human CXCR3 variants selected from CXCR3A and/or CXCR3alt, or does the claim encompass selecting CXCR3B as the variant? If the former, the claim should be amended to recite that the cells express “one or more human CXCR3 variants selected from CXCR3A and/or CXCR3alt” (if desired, CXCR3B could be included in a dependent claim, i.e. the cells further express CXCR3B). If the latter interpretation is desired, the last wherein clause should be removed from the claim.
Claim 15 is also indefinite in the recitation of “CXCR3alt+”. The instant specification discloses CXCR3alt refers to a splice variant mRNA product that produces a truncated polypeptide (CXCR3alt is known in the art, see prior art references cited below, for example). However, the recitation of the “+” renders the claims indefinite since it is not clear whether this limits the claim is some way. For example, does it refer to a particular level of expression or a particular type of CXCR3alt? The specification does not define what is meant by expression of “CXCR3alt+”, and the scope of the claims cannot be establish. For the purposes of examination, the claims are being interpreted as encompassing cells expressing CXCR3alt as the type of CXCR3 variant.
Claim 17 is indefinite, since it recites that the preparation of cells comprises “any one of the modified immune cells as specification in claim 1”. As an initial matter, claim 1 is directed to a method of treatment and not modified immune cells. Furthermore, it is unclear what features from claim 1 are required. Would including CD3+ cells meet the limitation? CD8+ memory T cells? Do the claim require that the cells have a transgene? The scope of the claim is unclear and indefinite. For the purposes of examination. the claim is being treated as being directed to the isolated cells according to claim 15, comprising at least 50% of modified CD3+ T cells, wherein the modified CD3+ T cells express a CXCR3 transgene encoding the human CXCR3 variant.
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.
Claim 17 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 17 is directed to a product, but depends from claim 15, which is a method. Therefore, claim 17 does not include all the limitations of claim 15 (the claim only requires a product and would not require the particular treatment method steps of the claim from which it depends, for example). 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.
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.
Claims 15-17 and 19 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon (product of nature) without significantly more. The claim(s) recite(s) immune cells expressing one or more human CXCR3 variants. This judicial exception is not integrated into a practical application because said immune cells are products of nature. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons set forth below.
Laws of nature and natural phenomena, as identified by the courts, include naturally occurring principles/relations and nature-based products that are naturally occurring or that do not have markedly different characteristics compared to what occurs in nature. The courts have often described these exceptions using other terms, including “physical phenomena,” “scientific principles”, “natural laws,” and “products of nature.” Product of nature exceptions include both naturally occurring products and non-naturally occurring products that lack markedly different characteristics from any naturally occurring counterpart. See, e.g.,Ambry Genetics, 774 F.3d at 760, 113 USPQ2d at 1244 (“Contrary to Myriad's argument, it makes no difference that the identified gene sequences are synthetically replicated. As the Supreme Court made clear, neither naturally occurring compositions of matter, nor synthetically created compositions that are structurally identical to the naturally occurring compositions, are patent eligible.”). Thus, a synthetic, artificial, or non-naturally occurring product such as a cloned organism or a human-made hybrid plant is not automatically eligible because it was created by human ingenuity or intervention. See, e.g.,In re Roslin Institute (Edinburgh), 750 F.3d 1333, 1337, 110 USPQ2d 1668, 1671-72 (Fed. Cir. 2014) (cloned sheep); cf. J.E.M. Ag Supply, Inc. v. Pioneer Hi-Bred Int’l, Inc., 534 U.S. 130-132, 60 USPQ2d 1868-69 (2001) (hybrid plant). Instead, the key to the eligibility of all non-naturally occurring products is whether they possess markedly different characteristics from any naturally occurring counterpart. See MPEP 2106.04(b).
In the instant case, the claims are directed to compositions of matter as set forth in Step 1 of the subject matter eligibility test (see MPEP 2106). Regarding step2A, prong 1, the claims recite a preparation of immune cells expressing one or more human CXCR3 variants selected from CXCR3A, CXCR3alt, and/or CXCR3B. Naturally occurring human CXCR3 is expressed as 3 naturally occurring isoforms that are splice variants, CXCR3A, CXCR3alt, and CXCR3B (see Reynders, 2019 and Vollmer, 2021, of record, and the instant specification page 4). Furthermore, immune cells, including T cells or CD8+ memory T cells naturally express said CXCLR3 variants (see Vollmer, 2021). Thus, the claims would encompass naturally occurring immune cells, such as CD8 memory T cells, that naturally express said CXCR3 splice variants like CXCR3alt. The present claims recite a preparation of said immune cells are “isolated” with certain percentages of said cells. However, the fact that the cells have been isolated does not impart any marked difference in structure or function. Therefore, the claims as a whole do not integrate the judicial exception into a practical application, since there is no difference in structure or function from naturally occurring immune cells. Claim 17, which depends from claim 15 recites the limitation of a “modified” T cell comprising a “transgene” encoding a “recombinant’ CXCR3 variant. These are product by process limitation explaining how the T cells are made. During examination, a product-by-process claim is not limited to manipulations of the recited steps, but instead is only limited to the structure implied by the steps. The instant specification discloses on page 9 that a “transgene” encompasses, for example, an mRNA. Naturally occurring T cells expressing said CXCR3 variants would comprise an mRNA encoding said variants (see Reynders), and therefore the limitation of a “transgene” does not impart any markedly different characteristic as compared to naturally occurring T cells. Therefore, regarding step 2A prong two and step 2B, the claims do not recite additional elements that integrate the judicial exception into a practical application, nor do the claims recite any additional elements that amount to significantly more than the judicial exception.
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(s) 15-17 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Dar, 2006, as evidenced by Ehlert, 2004 (both of record).
Dar teaches T cells engineered (i.e. modified) to express a human CXCR3 transgene producing a recombinant CXCR3 (see page 469 and 472, in particular). Dar teaches that doing so is advantageous to dissect the mechanisms of CXCR3 signaling, since there can be variation in expressed levels of CXCR3 (see page 472, in particular). Dar teaches a preparation wherein 99% of the T cells express the CXCR3 transgene (See Fig. 2, in particular). As evidenced by Ehlert, whenever CXCR3 is recombinantly constructed and introduced into cell and transcribed, the CXCR3-alt message is also generated (See page 6238, in particular). Thus, the human CXCR3 transgene taught in Dar would necessarily express the CXCR3alt variant. Ehlert teaches that the T cells are Jurkat T cells, which are inherently CD3+ and wer also derived from patient with leukemia (i.e. from a cancer patient sample) .
Claim(s) 15-17 and 19 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Itzhaki, Feb. 2020, as evidenced by Vollmer, 2021 (of record).
Itzhaki teaches an isolated preparation of human immune cells comprising a CAR transgene, wherein the immune cells comprise 87% CXCR3+CD3+ T cells and 52.6% CD8+CXCR3+ T cells (i.e. they express human CXCR3, see Table 3, in particular). Itzhak also teaches another embodiment of human tumor infiltrating lymphocyte preparation wherein 86% of the T cells express CXCR3, and wherein said preparation comprises 63% CD8+ memory T cells (i.e. at least 50% of the CXCR3 expressing cells are CD8+ memory cells, see Table 3, in particular). Itzhaki teaches that the cells are derived from a cancer patient sample (See Tables in particular). The instant specification on page 3 teaches that in humans, three CXCR3 isoforms are expressed, CXCR3A, CXCR3B and CXCR3alt (see also Vollmer, in humans CXCR3 is expressed as 3 possible isoforms, CXCR3A, CXCR3B and CXCR3alt). Therefore, the human CXCR3 expressed by the T cells of Izhaki would necessarily be a “variant” selected from CXCR3A, CXCR3B and/or CXCR3alt. Additionally, as evidenced by Vollmer, CD8 memory T cells and TIL inherently express CXCR3alt (see Fig. 2 and page 9, in particular). Thus, the CXCR3+ T cells of Itzhaki inherently express CXCR3alt, in particular.
Regarding claim 17, the limitation that the cells are “modified” with a “transgene” expressing a “recombinant’ protein comprising the human CXCR3 variant, this refers to a product by process limitation explaining how the cells are made. However, during examination, a product-by-process claim is not limited to manipulations of the recited steps, but instead is only limited to the structure implied by the steps. The instant specification discloses on page 9 that a “transgene” encompasses, for example, an mRNA. The T cells of tzhaki would inherently express said CXCR3 variants from an mRNA (i.e. a “transgene”), and the T cells of the prior art are structurally and functionally identical to those of the instant claims.
Claim(s) 15-17 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO2018152572, as evidenced by Ehlert, 2004 (both of record).
WO2018152572 teaches a preparation of isolated T cells (i.e. CD3+ cell), wherein the T cells are engineered to express a transgene encoding a chemokine receptor, wherein said T cells engineered to express the chemokine receptor comprise at least 95% of the cells in the preparation (See paragraphs 81, 96-97, 176-181 in particular). WO2018152572 teaches that the nucleic acid can encode chemokine receptor can be CXCR3, and in particular can be the human CXCR3 gene or the mRNA sequence NM_001504.1, i.e. human CXCR3A (see paragraph 99-100 in particular). As evidenced by Ehlert, whenever CXCR3 is recombinantly constructed and introduced into cell and transcribed, the CXCR3-alt message is also generated (See page 6238, in particular). Thus, the CXCR3 engineered T cells would also inherently express the CXCR3alt variant.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 15-17 and 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO2018152572, in view of Itzhaki, Feb. 2020, and Ehlert, 2004 (of record).
The teachings of WO2018152572 are described above. WO2018152572 also teaches that the T cells can be CD8+ CAR T cells. WO2018152572 also teaches that in certain embodiments, the CXCR3 expressed in the T cells can respond to a chemokine expressed by cells associated with cancer, wherein the chemokine comprises one or more of CXCL4, CXCL9, CXCL10, and CXCL11, and CXCL13 (see paragraph 81, in particular).
WO2018152572 does not explicitly teach CD8+ memory T cells.
Itzhaki teaches that CD8+ CAR T cell preparations typically comprise at least 50% CD8+ memory T cells (See Table 3, in particular).
Ehlert teaches a transgene encoding CXCR3alt that can be used to engineer cells to express a recombinant CXCR3alt. Ehlert teaches that CXCR3alt selectively induces chemotaxis in response to CXCL11 only, whereas the other CXCR3 isoforms induce chemotaxis to CXCL9, CXCL10, and CXCL11 (see page 6238, in particular).
Thus, it would be obvious to the ordinary artisan that the CD8+ CAR T cells populations engineered to express CXCR3 of WO2018152572 would comprise at least 50% memory CD8+ T cells, since Itzhaki teaches that CAR engineered CD8+ T cell populations typically comprise more than 50% memory CD8+ T cells. This is pertinent to claim 19.
Furthermore, even though the limitations of CXCR3alt are inherent in WO2018152572 for the reasons set forth above, they would also be obvious. For example, the ordinary artisan would be motivated to introduce a CXCR3alt transgene, as taught by Ehlert, into the CAR T cells of WO2018152572, in order to provide responsiveness to one chemokine, CXCL11, as suggested by WO2018152572. The ordinary would be motivated to do so with a reasonable expectation of success because WO2018152572 teaches that one can engineer CXCR3 expression for providing responsiveness to one or more chemokines, including CXCL11. Thus, it would be obvious that when engineering responsiveness to one chemokine, such as CXCL11 is desired, one would use the transgene encoding the CXCR3alt isoform, since Ehlert teaches that it selectively induces chemotaxis in response to CXCL11 only.
Claim(s) 15-17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Dar, in view of Ehlert, 2004 (both of record).
The teachings of Dar are described above. Even though the limitations that the CXCR3 expresses one or more CXCR3A, CXCR3B, and CXCR3alt are inherent for the reasons set forth above, it would also be obvious to use a transgene encoding CXCR3alt based on the teachings of Ehlert.
Ehlert teaches transgenes encoding CXCR3alt or full length CXCR3 that can be used to express a recombinant CXCR3 or a CXCR3alt for studying their signaling properties in cells or for providing responsiveness to different chemokines.
Thus, the ordinary artisan would be motivated to produce the CXCR3 expressing T cell preparations of Dar, using a CXCR3alt transgene, as taught by Ehlert. The ordinary would be motivated to so with a reasonable expectation of success in order to study the different signaling properties of each receptor in Jurkat T cells or to provide responsiveness to different chemokines.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY E JUEDES whose telephone number is (571)272-4471. The examiner can normally be reached on M-F from 7am to 3pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached on 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Amy E. Juedes
Patent Examiner
Technology Center 1600
/AMY E JUEDES/Primary Examiner, Art Unit 1644
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