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 .
Priority
Acknowledgement is made of Applicants’ claim for benefit of U.S. Provisional Application No. 63/277,893 (filed 11/10/2021).
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 05/19/2026 in response to a Restriction requirement is acknowledged.
Claims 1-165 read on the elected invention.
Claim Objections
Claims 7-78 and 85-165 are objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim cannot depend from any other multiple dependent claim. See MPEP § 608.01(n). Accordingly, the claims have not been further treated on the merits.
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.
Claims 1-6 and 79-84 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 instant claims are directed to a method of expanding a natural killer (NK) cell comprising contacting said cell with (i) a first polypeptide comprising B7-H6 or a functional fragment thereof, or an anti-NKp30 antigen-binding domain, (ii) a second polypeptide comprising 4-1BBL or a functional fragment thereof, (iii) a third polypeptide comprising ICAM-1 or a functional fragment thereof; and, in the case of claim 79 and its dependent claims, (iv) a fourth polypeptide comprising IL-21 or a functional fragment thereof.
The issue at present is the scope the functional fragment limitation imposes on the instant claims. A polypeptide fragment per se includes individual amino acids of the polypeptide; a fragment covers an extraordinarily large number of molecules. The claims do restrain the scope of this limitation by requiring the fragment to be functional. Under broadest reasonable interpretation, this is understood to mean the fragment has the immune activity function of its respective full-length polypeptide (e.g., the ability to bind to its cognate binding partner); this interpretation is supported by par. 0061 of the specification, “…retains at least 80%...of one activity (e.g., cognate binding partner (e.g., receptor) binding activity) of the reference polypeptide.” Thus, functional fragments of each of B7-H6, 4-1BBL, ICAM-1, and IL-21 are considered a genus of molecules. (NKp30 is not included in this rejection, as the anti-NKp30 antigen-binding domain is not followed by a functional fragment limitation.)
To satisfy the written description aspect of 35 U.S.C. 112(a) for a claimed genus of molecules, it must be clear that: (1) the identifying characteristics of the claimed molecules have been disclosed, e.g., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed cor-relation between function and structure, or by a com-bination of such identifying characteristics; or (2) a representative number of species within the genus must be disclosed. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Now, regarding (1): There is no clear definition of functional fragments set forth in the disclosure. In the instant specification (pg. 22; par. 5), Applicants recite:
The term "functional fragment" means a portion of an amino acid sequence (e.g., of a polypeptide) that is substantially identical to, but shorter in length than, a reference polypeptide that retains at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of one activity (e.g., cognate binding partner (e.g., receptor) binding activity) of the reference polypeptide. A fragment can include an N-terminal truncation, a C-terminal truncation, or both N-terminal and C-terminal truncations relative to a reference polypeptide.
However, the guidance set forth above is not sufficient written description support. The specification does not teach a specific core structure (i.e., a conserved sequence) which correlates to the function of the polypeptides of the disclosure. Which structures or residues are necessary for a fragment of a B7-H6, 4-1BBL, ICAM-1, or IL-21 polypeptide to be functional? What are the guidelines for determining if a peptide fragment is “substantially identical” to the reference polypeptide? Are there particular cellular domains necessary in order for the fragment to serve its purpose in the methods of the instant claims? The instant specification provides amino acid sequences for these polypeptides (see e.g., pgs. 42-49), but lacks clear guidance or teaching regarding which structural components are required.
Regarding (2): Applicants have failed to provide disclosure of a representative number of species of the claimed genera of the instant claims. For example, the B7-H6 amino acid sequence (UniProtKB Accession No. Q68D85) contains 454 amino acids. Using the Sum of Natural Numbers Formula to calculate x possible contiguous fragments for n residues in the sequence:
x
=
n
n
+
1
2
There are 103,284 possible fragments for the B7-H6 functional fragment genus. Applicants’ disclosure for B7-H6 polypeptides or fragments thereof is limited to seven species overall: two species of full-length B7-H6 polypeptides (human, rat); five species of extracellular domains (human, rat, truncated human, IgV-like human, IgV-like rat). This disclosure of five species of the larger B7-H6 functional fragment genus is not representative.
Likewise, Applicants’ disclosure for the remaining polypeptides is limited to: full-length 4-1BBL (human, rat, mouse), full-length ICAM-1 (human, rat, mouse), and full-length IL-21 (human, rat, mouse) polypeptides; extracellular domains of 4-1BBL (human, rat, mouse), and extracellular domains of ICAM-1 (human, rat, mouse) polypeptides. It is noted the specification only discloses full-length IL-21 polypeptides, not fragments or truncated molecules thereof. This limited disclosure is not considered to be representative of the full breadth of the genera, as currently claimed.
Now, following the above discussion and excluding IL-21, Applicants’ disclosure regarding (2) set forth above is considered a representative number of species if the required function of the polypeptide fragment is its ability to bind to its cognate binding partner. This is because a person having ordinary skill in the art would be able to envisage which fragments of these polypeptides are capable of binding to the respective cognate binding partner. As evidenced by Brandt, et al., the extracellular domain of NKp30 directly and selectively interacts with the extracellular domain of B7-H6 (pg. 1498; col. 1, par. 2. J Exp Med. 2009). Gilbreth, et al. discloses residues outside of the conserved extracellular domain (THD) of 4-1BBL are not required for binding to 4-1BB (Fig. 2. J Biol Chem. 2018). Bui, et al. evidences it is the extracellular Ig domains of ICAM-1 which bind to its cognate ligands LFA-1 and Mac-1 (pg. 788; par. 2.1. J Leukoc Biol. 2020). However, though claim interpretation may be aided by the entire disclosure, it is improper to import claim limitations from the specification; see MPEP 2111.01(II).
Therefore, Applicants’ disclosure has support for a polypeptide comprising B7-H6 or an extracellular or IgV-like domain thereof, a polypeptide comprising 4-1BBL or an extracellular domain thereof, a polypeptide comprising ICAM-1 or an extracellular domain thereof, and a polypeptide comprising IL-21; but not functional fragments thereof.
Thus, a person having ordinary skill in the art, looking to the instant specification, would not be able to determine that Applicants were in possession of the invention, as claimed, at the time the invention was made. Accordingly, the claims are considered to lack sufficient written description and are properly rejected under 35 U.S.C. § 112(a).
Claim Rejections - 35 USC § 112
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 and 79-84 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 1, 79: As discussed above, the instant claims recite the functional claim limitation functional fragment(s), wherein the function of said fragment(s) is not defined. Therefore, as a person having ordinary skill in the art would not immediately envisage the function(s) to which this limitation is directed, the metes and bounds of the instant claims are not clearly or precisely defined. Thus, the claims are rejected for indefiniteness.
Claims 2-6 and 80-84 depend from claims 1 or 79, inherit the respective deficiencies, and are likewise rejected for indefiniteness.
Claim Rejections - 35 USC § 102
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 1 is rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Muller, et al. (US 2015/0017721), as evidenced by Memmer, et al. (J Biol Chem. 2016) and Gilbreth, et al. (J Biol Chem. 2018).
Muller, et al. teaches an in vitro method for inducing proliferation of natural killer (NK) cells (Abstract).
Regarding claim 1: Muller, et al. teaches a method for the proliferation and expansion of NK cells (par. 0036), comprising contacting the cells with a nanomatrix in aqueous solution (par. 0044), and wherein the nanomatrix comprises at least two stimulatory agents (par. 0099). In an embodiment, the stimulatory agents are an anti-CD337 antibody (par. 0052), a CD137 ligand (par. 0099), and an ICAM-1 molecule (par. 0100). As evidenced by Memmer, et al., NKp30 is also known as CD337 (Abstract); thus, the anti-CD337 antibody reads on an anti-NKp30 antibody comprising an antigen-binding domain. As evidenced by Gilbreth, et al. the CD137 ligand (CD137L) is also known as 4-1BBL (pg. 9880; par. 1); thus, the CD137 ligand reads on 4-1BBL.
Therefore, the method of Muller, et al. anticipates the method of expanding an NK cell comprising: contacting an NK cell disposed in a liquid culture medium, in the absence of a feeder cell, with (i) a first polypeptide comprising B7-H6 or a functional fragment thereof, or an anti-NKp30 antigen-binding domain, (ii) a second polypeptide comprising 4-1BBL or a functional fragment thereof, and (iii) a third polypeptide comprising ICAM-1 or a functional fragment thereof, under conditions sufficient for expansion of the NK cell limitations recited in claim 1.
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.
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.
Claims 1-6 are rejected under 35 U.S.C. 103 as being unpatentable over Muller, et al. (US 2015/0017721), as evidenced by Memmer, et al. (J Biol Chem. 2016) and Gilbreth, et al. (J Biol Chem. 2018).
The teachings of Muller, et al. are set forth above; claim 1 is anticipated by the same.
Regarding claim 2: Following the above discussion, Muller, et al. teaches an embodiment wherein a nanomatrix comprising a first stimulating agent is contacted with NK cell, followed by subsequent contact with a second or more (multiple) co-stimulating agents added as soluble agents to optimize or support activation induced by the nanomatrix with the first agent attached thereto (pars. 0115-0116).
Muller, et al. does not explicitly teach the limitations recited in claim 2.
However, periodically re-contacting the NK cells with the polypeptides would have been routinely optimized by one having ordinary skill in the art based on the expansion of the NK cells. Muller, et al. clearly teaches the nanomatrix comprising its active agents is provided in an optimizable format effective to achieve activation, proliferation, and expansion of NK cells; subsequent contact with active agents, as needed after initial contact, is clearly encompassed by the disclosure. This means the contact between the NK cells and active agents (i.e., the polypeptides) were result effective variables. Result effective variables would be optimized by routine experimentation by one having ordinary skill in the art, rendering obvious the limitations recited in claim 2. See MPEP 2144.05(II)(A).
Regarding claim 3: Following the above discussion, Muller, et al. teaches the method of the disclosure can be used for long-term NK cell in vitro expansion (par. 0031). While the disclosure does not explicitly recite expanding NK cells for 30 days, Muller, et al. compares its method to other long-term culturing of NK cells, comprising expanding the cells for four weeks (par. 0010).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art to have performed the method of Muller, et al. for 30 days. This conclusion of obviousness is based on the ‘teaching, suggestion, or motivation rationale’. One would have been motivated to do so because, as disclosed by Muller, et al., the method is useful for expansion of therapeutic NK cells for cancer patients (par. 0133); thus, it would have been obvious to the skilled artisan to culture the NK cells for 30 days in order to generate a sufficient number of cells for the therapeutic treatment. This renders obvious the wherein the method is performed over about 30 days limitation recited in claim 3.
Further, for the same reasons set forth above in the rejection of claim 2, the days on which the re-contacting step with the active agents (i.e., the polypeptides) is performed would have been routinely optimized by one having ordinary skill in the art. This renders obvious the wherein the re-contacting step is performed at about day 10 and at about day 20 after the contacting step limitation recited in claim 3.
Regarding claims 4-6: Muller, et al. teaches an embodiment wherein NK cells cultured with nanomatrices conjugated to CD2 and CD335 antibodies are cultured and expanded for 19 days (par. 0146). While this example does not use the polypeptide embodiments set forth above, it nevertheless would have been prima facie obvious to a person having ordinary skill in the art to have used the method of Muller, et al. for culturing the NK cells for 19 days. This conclusion of obviousness is based on the ‘substitution rationale’; the use of a nanomatrix comprising an anti-CD337 antibody (i.e., an anti-NKp30 antibody comprising an antigen-binding domain), a CD137 ligand (i.e., 4-1BBL), and an ICAM-1 molecule in place of a nanomatrices conjugated to CD2 and CD335 antibodies is a predictable use of prior art elements according to their established functions as nanomatrices comprising NK stimulatory agents, leading to the predictable result of expansion of NK cells. As the Muller, et al. disclosure teaches both of these nanomatrix embodiments, the skilled artisan would have more than a reasonable expectation of success. This rationale aligns with the principle of a simple substitution of one known element for another to obtain predictable results; see MPEP 2143(I)(B). Thus, the modified method of Muller, et al. renders obvious:
the wherein the method is performed over about 1 day to about 30 days limitation recited in claim 4;
the wherein the method is performed over about 5 days to about 30 days limitation recited in claim 5; and
the wherein the method is performed over about 10 days to about 30 days limitation recited in claim 6.
Claims 1-6 and 79-84 are rejected under 35 U.S.C. 103 as being unpatentable over Kevlahan, et al. (US 2020/0085971); as evidenced by Memmer, et al. (J Biol Chem. 2016), Gilbreth, et al. (J Biol Chem. 2018), and Bui, et al. (J Leukoc Biol. 2020).
Kevlahan, et al. teaches a hydrogel complex that can bind to and modulate a desired immune cell (Abstract).
Regarding claims 1, 79: Kevlahan, et al. teaches a method for generating expanded and/or activated immune cells using a biocompatible hydrogel complex capable of binding to, activating, and expanding said immune cell (par. 0006) in culture media (par. 0113), wherein the immune cell is a natural killer (NK) cell (par. 0017). The complex comprises a hydrogel and a binding moiety configured to bind a cell surface component of the immune cell (par. 0007); there may be one, two, three, or more binding moieties (par. 0012). Disclosed is an embodiment wherein the binding moiety is an anti-CD337 antigen-binding fragment (par. 0013) and IL-21 (par. 0016), and wherein the cell surface component is LFA-1 and CD137 (par. 0010). As evidenced by Memmer, et al., NKp30 is also known as CD337 (Abstract); thus, the anti-CD337 antigen-binding fragment reads on an anti-NKp30 antigen-binding domain. Therefore, the method of Kevlahan, et al. reads on:
the method of expanding an NK cell comprising: contacting an NK cell disposed in a liquid culture medium, in the absence of a feeder cell, with (i) a first polypeptide comprising an anti-NKp30 antigen-binding domain under conditions sufficient for expansion of the NK cell limitations recited in claim 1; and
the method of expanding an NK cell comprising: contacting an NK cell disposed in a liquid culture medium, in the absence of a feeder cell, with (i) a first polypeptide comprising an anti-NKp30 antigen-binding domain, and (iv) a fourth polypeptide comprising IL-21 or a functional fragment thereof, under conditions sufficient for expansion of the NK cell limitations recited in claim 79.
Further, as evidenced by Gilbreth, et al., CD137 and its ligand, CD137L, are also known as 4-1BB and 4-1BBL. As evidenced by Bui, et al., LFA-1 is the cognate ligand of ICAM-1 (pg. 788; par. 2.1).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art to have modified the method of Kevlahan, et al. by including 4-1BBL and ICAM-1 as binding moieties in the hydrogel complex. This conclusion of evidence is based on the ‘teaching, suggestion, or motivation rationale’. One would be motivated to do because Kevlahan, et al. teaches the hydrogel complex comprises binding moieties capable of binding to a cell surface component (par. 0007), and it would have been obvious to have used the cognate ligands which bind the LFA-1 and CD137 cell surface components. This results in the hydrogel complex further comprising 4-1BBL (i.e., the ligand of CD137/4-1BB), as well as ICAM-1 (i.e., the ligand of LFA-1). Thus, this modified method of Kevlahan, et al. renders obvious the remaining (ii) a second polypeptide comprising 4-1BBL or a functional fragment thereof, and (iii) a third polypeptide comprising ICAM-1 or a functional fragment thereof limitations recited in claims 1 and 79.
Regarding claims 2, 4-6, 80, 82-84: Following the above discussion, Kevlahan, et al. teaches an embodiment wherein the complex is dissolved and reapplied multiple times over the course of the expansion protocol; in an embodiment, the expansion protocol is for 21 days or more (par. 0114). This reads on:
the wherein after the contacting step the method comprises periodically re-contacting the NK cell with the first polypeptide, the second polypeptide, and the third polypeptide limitation recited in claim 2;
the wherein the method is performed over about 1 day to about 30 days limitation recited in claim 4;
the wherein the method is performed over about 5 days to about 30 days limitation recited in claim 5;
the wherein the method is performed over about 10 days to about 30 days limitation recited in claim 6;
the wherein after the contacting step the method comprises periodically re-contacting the NK cell with the first polypeptide, the second polypeptide, the third polypeptide, and the fourth polypeptide limitation recited in claim 80;
the wherein the method is performed over about 1 day to about 30 days limitation recited in claim 82;
the wherein the method is performed over about 5 days to about 30 days limitation recited in claim 83; and
the wherein the method is performed over about 10 days to about 30 days limitation recited in claim 84.
Regarding claims 3, 81: Following the above discussion, Kevlahan, et al. teaches an embodiment wherein the expansion protocol is performed for 3 to 4 weeks (par. 0114); this renders obvious the wherein the method is performed over about 30 days limitation recited in claims 3 and 81. The disclosure does not explicitly recite which days to reapply the hydrogel complex.
However, Kevlahan, et al. clearly teaches the complex may be dissolved and reapplied as necessary to overcome constraints on physical space or media nutrient depletion (par. 0114); further, disclosed is an embodiment wherein the expansion protocol is performed until the desired phenotype of the NK cell is acquired (par. 0116). Thus, Kevlahan, et al. implicitly teaches the contacting of the NK cells with the hydrogel complex is a result effective variable. Result effective variables would be optimized by routine experimentation by one having ordinary skill in the art. See MPEP 2144.05(II)(A). This renders obvious the remaining wherein the re-contacting step is performed at about day 10 and at about day 20 after the contacting step limitations recited in claims 3 and 81.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GINA PRONZATI whose telephone number is (571)270-5725. The examiner can normally be reached Monday - Friday 9:00a - 5:00p ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, CHRISTOPHER BABIC can be reached at (571)272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/GINA PRONZATI/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633
Prosecution Insights