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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-13 in the reply filed on 04/16/2026 is acknowledged.
Claims 14-15 and 27-30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 04/16/2026.
Status of Claims
Claims 16-26 were previously cancelled, in the amendment filed 09/13/2023. Claims 1-15 and 27-30 are pending. Claims 14-15 and 27-30 are withdrawn. Claims 1-13 will be examined on the merits.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. PCT/IB2021/058083, filed on 09/04/2021. For the purposes of applying prior art, the EFD is 09/04/2020.
Information Disclosure Statement
The Information Disclosure Statements filed on 1/11/2024, 01/06/2025, 04/29/2025, 12/02/2025, and 04/16/2026 have been considered. Signed copies are enclosed.
Claim Rejections - 35 USC § 112
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 12 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 12 recites "the isolated composition of claim 1, for use in a therapy". The intended use of the composition does not hold patentable weight. See MPEP §2103/2111. Therefore, claim 12 does not recite any further meaningful limitation to the composition of claim 1. 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.
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, 3-6, and 9-13 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.
The term “CD56bright” in claim 1 is a relative term which renders the claim indefinite. The term “CD56bright” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. While known in the art, the term “CD56” is not clearly defined enough to determine the scope of the claim. There is no definition provided in the claim. The specification attempts to recite a definition by process on page 19, lines 6-13, reciting “CD56 surface expression can be determined using methods known in the art, such as through analysis of the staining intensity via flow cytometry. Dividing cells into CD56bright and CD56dim is understood in the art…Such methods compare the sample population to a reference population of known CD56 expression levels, such as a cell population containing NK cells. NK cells have distinct CD56 expression levels that can be identified as bright and dim, so by establishing gating strategies using this reference population, the sample population can also be sorted into CD56bright and CD56dim fractions for the purposes of this invention.” The same paragraph points to the reference of Van Acker et al. (2017) Front. lmmunol. 8: 892. Neither the specification or the source defines a threshold that determines if a cell is “CD56bright” or “CD56dim”. Indeed, gating strategies via flow cytometry can be subjective, and no guidance is given, in the specification or in the source, on how to accurately gate for these populations. The ‘sample population’, referenced in the specification is not provided, nor are any parameters defining it beyond “a population containing NK cells”. Depending on the sample population used, the gating parameters selected, or any other factor, the line between “CD56bright” and “CD56dim” could be construed differently. Furthermore, the specification refers to cells that are CD56+ and CD56- (page 86). It is unclear if these cell populations also correspond to CD56bright and CD56dim populations or not. If they do not, there is no defined way to distinguish between CD56dim and CD56- cells. Small changes in parameters could lead to a CD56dim cell being characterized as CD56-. Finally, the source, Van Acker et al., only refers to NK cells as being CD56bright, whereas the claim refers to γδ T cells as CD56bright. Van Acker et al. only refers to γδ T cells as CD56+. It is unclear if γδ T cells also express the varied levels of CD56 or if it is only NK cells. For the purposes of applying prior art, CD56+ and CD56bright will be interpreted as synonymous, and CD56- and CD56dim will be interpreted as synonymous. Applicant may point to specific places in the specification and/or Van Acker et al. source that provides a specific, measurable definition for CD56bright in order to overcome this rejection.
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.
Claim 13 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of killing tumor cells, does not reasonably provide enablement for a method of treating cancer, an infectious disease, or an inflammatory disease. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized in In re Wands (858 Fed 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, limited working examples, the unpredictability in the art, and the amount of experimentation required to enable one of skill in the art to make and use the claimed invention.
Claim 13 is broadly drawn to a method of treating cancer, an infectious disease, or an inflammatory disease in a subject, comprising administering to the subject the isolated composition of NK and γδ T cells. The specification defines treating as “reducing the frequency and/or severity of at least one sign or symptom of the disease or disorder experienced by a subject” (page 17, line 20-21). The specification only provides a definition for cancer, as “the abnormal growth or division of cells” (page 17, line 22). The “Treatment Methods” section of the specification, beginning page 75, indicates that the composition would be of use in infectious disease, as NK cells are known to be potent in fighting bacteria, viruses, and fungi, Vδ1 T cells are important for protection against CMV, and Vδ2 T cells are important for mycobacterial and protozoa infections, among others. There are no sources cited wherein administration of these cells assisted in treating any of these diseases. The only working examples provided showing the efficacy of the cell composition are Example 4, Example 8, and corresponding Figures 6, 11, 13, 16, and 19, all demonstrating in vitro cytotoxic effects of the cells. No working examples providing “treatment” are provided.
While the roles of NK cells and γδ T cells have been fairly extensively defined in cancer and infectious disease, the art regarding immunotherapies comprising NK cells and γδ T cells is limited. Most therapeutic uses of allogenic NK or γδ T cells are still in early clinical stages and have encountered problems. Lamers-Kok et al. (J Hematol Oncol 15, 164 (2022)) discuss the clinical development of NK cell therapies. While NK cell therapies seem promising, common issues, such as limited persistence, infiltration, and low efficacy are often observed (page 45, right column). Wu et al. (Int J Biol Sci. 2014 Jan 10;10(2):119-35) reviews similar issues with γδ T cell therapies, including short-term responses and significant adverse events (pages 129-130, “Obstacles” section), and Silva-Santos et al. (Nat Rev Cancer 19, 392–404 (2019)) outlines the limited in vivo proof-of-concept studies involving γδ T cell therapies and insufficiencies of current models (see page 401, left column).
Accordingly, in view of the art and in the absence of substantive direction or guidance in the instant specification, one of skill in the art would have to perform extensive experimentation in order to effectively administer the claimed composition in order to treat cancer, infectious disease, or inflammatory disease. Given the resource-intensive nature of the required experimentation, the skilled artisan would reasonably conclude that such experimentation would be unnecessarily, and improperly, extensive and undue.
In view of the Wands factors as discussed above, one of ordinary skill in the art would have to engage in undue experimentation to practice the full scope of the instant claimed invention. As such, instant claim 13 does not meet the scope of enablement requirement of 35 USC § 112(a).
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.
Claims 1-12 are rejected under 35 U.S.C. 101 because the claimed invention is directed to natural product without significantly more. The claim(s) recite(s) an isolated composition comprising NK and γδ T cells. This judicial exception is not integrated into a practical application because there is no method of using recited in claims 1-12. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the cells as claimed are substantially the same as those that occur in nature, and no additional elements are required by the dependent claims.
Applicant’s claims recite compositions comprising various immune cells. Therefore, the claims are directed to a composition of matter, one of the statutory categories of invention (Step 1: YES).
The claims are then analyzed to determine whether they are directed to any judicial exception. More specifically, the claims are drawn to an isolated composition comprising Natural Killer (NK) cells and γδ T cells, wherein at least 40% of the γδ T cells present in the composition are CD56bright in claim 1 or 50% are CD56+ in claim 2, and an isolated composition comprising NK cells, γδ T cells, Vδ1 T cells, and Vδ2 T cells in claim 7. Claims 3-6 and 8-12 further limit these claims with proportions of cells and expression of molecules (CD56, NKp30, CD27) by the cells. As evidenced by Poli et al. (Immunology, (2009) 126: 458-465), Paul et al. (Journal of Leukocyte Biology, (2015) 97(2):259–271), and Hudspeth et al. (Blood, (2012) 119(17):4013-4016), these expression markers are commonly found on NK cells in nature. Because there is no difference between the claimed and naturally occurring cells, the claimed cells do not have markedly different characteristics, and thus are a “product of nature” exception. In re Roslin Institute (Edinburgh), 750 F.3d 1333, 1338-39 (Fed. Cir. 2014). Accordingly, claims 1-12 are directed to an exception (Step 2A: YES).
Next, the claim as a whole is analyzed to determine whether any element, or combination of elements, is sufficient to ensure that the claim amounts to significantly more than the exception. Dependent claims specify embodiments wherein the cells are present in certain proportions; for example, claim 2 recites at least 50% of the cells express CD56. As cells can both express and not express CD56 in nature (see Poli et al. (abstract) and Paul et al. (Table 1)), any proportion of CD56+ to CD56- cell is still a natural product. Similarly, Vδ1 and Vδ2 cells are naturally occurring (see Paul et al., Table 1 and page 259, right column) and can be CD27+ or CD27- (Paul et al., page 260, right column), and/or NKp30+ or NKp30- (see Hudspeth et al., abstract, introduction). Therefore, dependent claims 2-6, 8-10, and 12 also recite only natural products. Claim 11 is drawn to the isolated composition of claim 1 comprising engineered NK and γδ T cells. The specification defines engineered NK cells and γδ T cells on page 22, as cells ‘engineered to express one or more transgenes’ (line 16). As one of the possible transgenes named as an example in line 18 includes NKp30, which is naturally expressed by both NK and γδ T cells (see Poli et al., page 460, right column and Hudspeth et al., abstract, introduction), there exists an embodiment when the engineered cells still have no markedly different characteristics from a naturally occurring NK or γδ T cell, and thus are still directed to a natural product. Therefore, no additional elements are recited that amount to significantly more than the judicial exception.
Taken together, the isolated compositions of claims 1-12 do not have markedly different characteristics from what occurs in nature, and are a “product of nature” exceptions. Thus, the claims are rejected under 35 U.S.C. 101.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-8 and 11-13 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by US 2020/0032211 A1, Quintarelli et al., published 1/30/2020.
The instant claims are drawn to isolated compositions comprising NK cells and γδ T cells. Claim 1 is drawn to an isolated composition comprising NK cells and γδ T cells wherein at least 40% of the γδ T cells are CD56bright. Claims 3-6 further limit claim 1, reciting that 90% of the cells present in the composition consist of NK cells and γδ T cells, at least 30% of the cells are γδ T cells, at least 30% of the cells are NK cells, and the γδ T cells comprise Vδ1 and Vδ2 T cells. Claims 9-11 also further limit claim 1, reciting that the γδ T cells comprise Vδ1 T cells, and that the Vδ1 T cells express either NKp30 (15%) or CD27 (less than 50%), or that the isolated composition comprises engineered NK cells and γδ T cells. Claims 12 and 13 are drawn to intended uses of the composition of claim 1. Claim 2 is another isolated composition comprising NK cells and γδ T cells, wherein at least 50% of the γδ T cells express CD56. Claim 7 is drawn to another isolated composition comprising cells, wherein at least 90% of the cells consist of NK cells and γδ T cells, at least 10% of the cells are Vδ1 T cells, at least 5% are Vδ2 T cells, and at least 30% are NK cells.
Quintarelli teaches methods of making innate immune cell compositions containing gamma.delta (γδ) T cells and/or Natural Killer (NK) cells (abstract). Specifically, in example 12, Quintarelli teaches a composition of cells cultured in the presence of IL-15 for 7 days, wherein the composition has 60% CD56+ γδ T cells (therefore anticipating claims 1 and 2), 92.45% NK and γδ T cells (anticipating claim 3), 36.5% γδ T cells (anticipating claim 4), and 56.25% NK cells (anticipating claim 6) (See Table 3). Table 4 of Quintarelli expands on the populations of cells in table 3, and shows the same population comprises 97% Vδ1+ and Vδ2+ T cells (teaching claim 5). Quintarelli also teaches that the cells may be genetically engineered (see abstract, paragraphs [0004] and [0023]), thereby anticipating claim 11. Finally, claim 21 and paragraph [0050] teach a method for treating cancer or an infection comprising administering to a subject a therapeutically effective amount of a composition comprising NK and γδ T cells, anticipating claims 12 and 13.
Regarding the composition of claim 7, Quintarelli teaches, in example 12, a population of cells cultured in the presence of IL-15 and IL-2 for 20 days, wherein the composition comprises 99.55% NK and γδ T cells, 51.7% NK cells, 23.2% Vδ1 T cells, 21.3% Vδ2 T cells, and 77% CD56+ γδ T cells (tables 3 and 4), thereby teaching claims 7 and 8.
Claim Rejections - 35 USC § 103
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 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.
Claim(s) 1-13 are rejected under 35 U.S.C. 103 as being unpatentable over US 2020/0032211 A1, Quintarelli et al., published 1/30/2020 as evidenced by Van Acker et al., (2016) J Hematol Oncol 9, 101.
Quintarelli teaches methods of making innate immune cell compositions containing gamma.delta (γδ) T cells and/or Natural Killer (NK) cells. Specifically, in example 12, Quintarelli teaches a composition of cells cultured in the presence of IL-15 for 7 days, wherein the composition has 60% CD56+ γδ T cells (therefore teaching claims 1 and 2), 92.45% NK and γδ T cells (teaching claim 3), 36.5% γδ T cells (teaching claim 4), and 56.25% NK cells (teaching claim 6) (See Table 3). Table 4 of Quintarelli expands on the populations of cells in Table 3, and shows the same population comprises 97% Vδ1+ and Vδ2+ T cells (teaching claim 5). Quintarelli also teaches that the cells may be genetically engineered (see abstract, paragraphs [0004] and [0023]), thereby teaching claim 11. Finally, claim 21 and paragraph [0050] teach a method for treating cancer or an infection comprising administering to a subject a therapeutically effective amount of a composition comprising NK and γδ T cells, anticipating claims 12 and 13.
Regarding the composition of claim 7, Quintarelli teaches, in example 12, a population of cells cultured in the presence of IL-15 and IL-2 for 20 days, wherein the composition comprises 99.55% NK and γδ T cells, 51.7% NK cells, 23.2% Vδ1 T cells, 21.3% Vδ2 T cells, and 77% CD56+ γδ T cells (tables 3 and 4), thereby teaching claims 7 and 8.
Quintarelli does not explicitly teach a population of cells in which the γδ T cells comprise Vδ1 T cells wherein the Vδ1 T cells express either NKp30 (15%) or CD27 (less than 50%). Quintarelli does teach that the same condition of IL-15 treatment for 7 days results in 54.17% of γδ T cells expressing NKp30 in the table of paragraph [0157]. Assuming even distribution, this would indicate that over half of the Vδ1 T cells are expressing NKp30, a percentage significantly higher than 15%. Even if the distribution is not perfectly even, it is clear that the conditions of Quintarelli can results in NKp30+ γδ T cells, and routine optimization of culture conditions could result in a population of γδ T cells wherein at least 15% of the cells express NKp30.
Quintarelli is silent on the expression of CD27 in the disclosed cell populations. However, there is support in the art that culturing γδ T cells in the presence of IL-15 can result in a high percentage of CD27- γδ T cells (see Van Acker et al., (2016) J Hematol Oncol 9, 101, figure 4). Therefore, it is likely that the population of cells expanded in the presence of IL-15 did contain less than 50% of Vδ1 T cells expressing CD27.
Moreover, the differences between the percent of subgroups of Vδ1 T cells disclosed in Quintarelli and the ones recited in the claims seem to correspond to slight procedural changes and straightforward possibilities from which the skilled person would select, in accordance with circumstances, without the exercise of inventive skill, in order to solve the problem posed.
Therefore, claims 1-13 are prima facia obvious over Quintarelli in view of Van Acker et al., absent evidence to the contrary.
Conclusion
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/AMELIA STEPHENS/ Examiner, Art Unit 1645
/ANNE M. GUSSOW/ Supervisory Patent Examiner, Art Unit 1683
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