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 Application, Amendments and/or Claims
The amendment of 15 March 2024 has been entered in full. Claims 1-7 are cancelled.
Claims 8-11 are pending and under consideration in the instant application.
Information Disclosure Statement
The two information disclosure statements (IDS) submitted on 07 June 2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
The replacement drawings were received on 16 May 2024 and 15 March 2024. These drawings are acceptable.
Specification
1. The disclosure is objected to because of the following informalities:
1a. The disclosure is objected to because it contains three embedded hyperlinks and/or other form of browser-executable code (page 29, [[0075]). Applicant is required to delete the embedded hyperlinks and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Appropriate correction is required.
Claim Objections
2. Claims 8 and 9 are objected to because of the following informalities:
2a. In claim 8, line 4, there is an extraneous commas after “NKG2D” and before the period.
2b. In claim 9, line 3, the phrase “can be” should be amended to recite, “is”.
Appropriate correction is required.
Claim Rejections - 35 USC § 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.
3. Claims 8-11 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.
3a. Claims 8-11 are rejected as being indefinite because claim 8, lines 2-3 recites that a costimulatory domain is attached intracellularly to the modified NKG2D receptor. However, it is not clear from claim 8 and the specification if the costimulatory domain is a separate protein, attached possibly by covalent bonding. Or, is the costimulatory domain an additional domain that is part of or a fusion of the NKG2D receptor (i.e., the NK2GD of claim 1 that further comprises a costimulatory domain”)?
3b. The term “effector molecule” in claim 11 is a relative term which renders the claim indefinite. The term “effector molecule” 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. It is not clear what molecules are/are not encompassed by this term. It is also not clear what “effect” the molecule is to have upon the mammalian cell. For instance, does this term include antibodies, cytokines, hormones, chemokines, growth factors, small molecules, oligonucleotides, siRNA, etc.?
Claim Rejections - 35 USC § 112(d)
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.
4. Claims 9-11 are 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. Claims 9-11 do not further the limit the claimed non-natural, modified NKG2D receptor attached to a mammalian cell of claim 8. First, line 1 of each of claims 9-11 recites either “[t]he non-natural, modified α1-α2 domains” or “[t]he NKG2D-attached costimulatory domain” rather than the claimed “non-natural, modified NKG2D receptor attached to a mammalian cell of claim 8”. Second, even if the first line of the claims is amended to refer back the NKG2D receptor attached to a mammalian cell of claim 8, claims 9-11 still would not further limit claim 8. Claims 9-11 recite limitations regarding a heterologous molecule or atom that binds modified α1-α2 domains of the NKG2D receptor ligands and the molecule’s effects when delivered to a mammalian cell. Claims 9-11 do not recite any limitations that limit the claimed non-natural, modified NKG2D receptor attached to a mammalian cell.
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.
Claim Rejections - 35 USC § 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.
5. Claims 8-11 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 8, for example, is directed to a non-natural, modified NKG2D receptor attached to a mammalian cell wherein a costimulatory domain is attached intracellularly to the modified NKG2D receptor without the presence the presence of an active CD3-zeta domain, wherein the receptor binds non-natural, modified α1-α2 domains of NKG2D ligands but not natural ligands of NKG2D.
The specification of the instant application teaches that non-natural NKG2D receptors have been mutated at one or two specific sites, each of which results in compromised or loss of binding to all natural α1-α2 domains of NKG2D ligands (page 12, [0035]). The specification continues to disclose that the instant invention creates CARs (chimeric antigen receptors) that when attached to a mammalian cell surface provide a silenced receptor that serves as a surrogate high affinity receptor for the attachment to the cell surface of heterologous atoms or molecules (page 12, [0035]). The specification indicates that when the CD3-zeta domain of a direct activation-competent CAR is selectively inactivated, it can still act as a silent CAR and enable the cognate non-natural ligand-attached heterologous molecules that have defective binding to their respective natural receptor or receptor subunits to transmit signals to the cell via their respective other receptor subunits (page 13, [0037]; Example 8). The specification continues to teach that a functional costimulatory domain is required to enable a heterologous molecule to mediate its respective signal to the CAR cell (page 13, [0037-0038]; Example 8). The specification teaches the generation of three different NKG2D receptors with modified ectodomains: “Y152”; “Y199”; and “Y152/Y199” (double mutant) (pages 20-22, Example 1; Figure 1A). The specification also indicates that single amino acid substitutions are explored at residues 152 and 199 (page 21, [0059]). Alanine, serine, threonine, and valine do not impact assembly of the Fc-NKG2D molecule, although leucine results in highly aggregated material (pages 21-22, [0059]; Figure 18). Additionally, alanine, glutamate, and aspartate are not tolerated at position 199 (page 22, [0059]; Figure 18). The specification concludes that of the combinations of mutations explored, Y152A/Y199F, Y152S/Y199F, Y152T/Y199F, and Y152F/Y199F do not negatively impact dimer formation, whereas other combinations resulted in increased aggregation (page 22, [0059]). Further experiments in the specification indicate that single mutant NKG2D candidates have diminished binding of natural ligand, ULBP2 (page 25, [0066]; Figure 20) while all double mutant candidates (Y152A/Y199F; Y152S/Y199F; Y152T/Y199F; Y152V/Y199F) have eliminated to significantly reduced binding (page 25, [0066-0067]; Figures 19-20).
The state of the art teaches that key residues involved in the contact of human NKG2D receptor with ligands are mapped to amino acids 150-207 (Strong et al. (Adv Protein Chem 68: 281-312, 2004) see page 298, Figure 8). Additionally, Landgraf et al. (US 2018/0134765) disclose that amino acid substitutions Y199A and Y152A/Y199A in human NKG2D result in the loss of binding of both natural and non-natural α1-α2 domain ligands (page 13, [0091]). Culpepper et al. (Mol Immunol 48: 516-5423, 2011) disclose that mutations Y152F and Y152I of human NKG2D actually increase receptor affinity to natural ligand, MICA (page 519, column 1, 1st paragraph; Table 1).
It is noted that the instant specification does not provide a specific definition for a non-natural or modified NKG2D receptor and thus, the phrase is broadly interpreted by the Examiner as reading upon any NKG2D receptor that binds non-natural α1-α2 domains of NKG2D ligands (but not natural ligands). Therefore, the claims encompass an infinite number of NKG2D receptors with any number of modifications. However, the specification does not teach any non-natural, modified NKG2D receptor attached to a mammalian cell with the limitations recited in instant claims 8-11, other than a human NKG2D receptor comprising mutations at amino acid positions 152 and/or 199, wherein the amino acid at position 152 is replaced with alanine, serine, threonine, or valine and the amino acid at position 199 is replaced with phenylalanine.
The first paragraph of 35 U.S.C. § 112 "requires a 'written description of the invention' which is separate and distinct from the enablement requirement." Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563 (Fed. Cir. 1991). An adequate written description of a chemical invention "requires a precise definition, such as by structure, formula, chemical name, or physical properties." University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916, 927 (Fed. Cir. 2004); Regents of the Univ. of Cal. v. Eli Lilly & Co., Inc., 119 F.3d 1559, 1566 (Fed. Cir. 1997); Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993). "A description of what a material does, rather than of what it is, usually does not suffice." Rochester, 358 F.3d at 923; Eli Lilly, 119 F.3d at 1568. Instead, the "disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described." Id. In addition, possession of a genus "may be achieved by means of a recitation of a representative number of [compounds]... falling within the scope of the genus." Eli Lilly, 119 F.3d at 1569. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus. See Rochester, 358 F.3d at 927.
Thus, case law dictates that to provide evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include actual reduction to practice, disclosure of drawings or structure chemical formulas, sufficient relevant identifying characteristics (such as, complete or partial structure, physical and/or chemical properties, and functional characteristics when coupled with a known or disclosed structure/function correlation), methods of making the claimed product, level of skill and knowledge in the art, predictability in the art, or any combination thereof. In the instant case, claims 1-7 are genus claims because they are directed to any non-natural, modified NKG2D receptor from any species, with an infinite number of mutations/modifications (i.e., substitutions, insertions, deletions, post-translational modifications), in any amino acid position. The only factors present in the claims are (i) a structural characteristic of a non-natural, modified NKG2D receptor attached to a mammalian cell wherein a costimulatory domain is attached intracellularly to the modified NKG2D receptor (without an active CD3-zeta domain) and (ii) a functional characteristic of binding non-natural, modified α1-α2 domains of NKG2D ligands (but not natural ligands). There is no identification of any particular sequence or structure of a modified NKG2D receptor that must be conserved in order to provide the required function of binding non-natural, modified α1-α2 domains of NKG2D ligands (but not natural ligands). Thus, the claims are drawn to a genus of non-natural or modified (engineered) NKG2D receptors, with any number of mutations/modifications (i.e., substitutions, insertions, deletions, post-translational modifications), in any amino acid position, wherein the modified receptors bind non-natural, modified α1-α2 domains of NKG2D ligands (but not natural ligands).
The instant specification fails to disclose and there is no art-recognized correlation between the structure of the genus of non-natural, modified NGK2D receptor mutants, fragments, truncations, or analogs from any species and the desired function of binding non-natural, modified α1-α2 domains of NKG2D ligands (but not natural ligands). The specification does not describe which amino acids of an NKG2D receptor retain the recited functional characteristics of binding non-natural, modified α1-α2 domains of NKG2D ligands (but not natural ligands) (other than a modified human NKG2D receptor comprising mutations at amino acid positions 152 and/or 199, wherein the amino acid at position 152 is replaced with alanine, serine, threonine, or valine and the amino acid at position 199 is replaced with phenylalanine). In other words, the specification does not teach which amino acids can be deleted, substituted, and/or inserted in any NKG2D receptor that result in a receptor polypeptide that retains a specific activity (i.e., binding non-natural, modified α1-α2 domains of NKG2D ligands (but not natural ligands)). Therefore, the description of two modified human NKG2D receptor species, wherein the receptor binds non-natural, modified α1-α2 domains of NKG2D ligands (but not natural ligands), wherein said receptor comprises mutations at amino acid positions 152 and/or 199 of human NKG2D, and wherein the amino acid at position 152 is replaced with alanine, serine, threonine, or valine and the amino acid at position 199 is replaced with phenylalanine, is not adequate written description of an entire genus of non-natural, modified NKG2D receptors that bind non-natural, modified α1-α2 domains of NKG2D ligands (but not natural ligands).
The art recognizes that protein function cannot be predicted from structure alone (Bork, 2000, Genome Research 10:398-400; Skolnick et al., 2000, Trends in Biotech. 18(1):34-39, especially p. 36 at Box 2; Doerks et al., 1998, Trends in Genetics 14:248-250; Smith et al., 1997, Nature Biotechnology 15:1222-1223; Brenner, 1999, Trends in Genetics 15:132-133; Bork et al., 1996, Trends in Genetics 12:425-427). See also Tokuriki et al. (Current Opinion in Structural Biology 19: 596-604, 2009), who teach that mutations are generally destabilizing. For instance, Tokuriki et al. teach at page 596, right column, last paragraph, that “as mutations accumulate, protein fitness declines exponentially...or even more than exponentially...So by the time an average protein accumulates, on average, five mutations, its fitness will decline to <20%.” Further, at page 598, left column, last paragraph, Tokuriki et al. note that 50% of mutations are destabilizing, and >15% of mutations are highly destabilizing, and of the about 5% of mutations that are stabilizing values...many of these mutations result in inactive protein. Fenton et al. (Medicinal Chemistry Research 29:1133-1146, 2020) also state that while it is well known that most substitutions at conserved amino acid positions (which they call “toggle” switches) abolish function, it is also true that substitutions at nonconserved positions (which they call “rheostat” positions) are equally capable of affecting protein function. They conclude that substitutions at rheostat positions have highly unpredictable outcomes on the activities and specificities of protein-based drugs. Bhattacharya et al. (PLoS ONE 12(3): e0171355, 2017) state that the range of possible effects of even single nucleotide variations at the protein level are significantly greater than currently assumed by existing software prediction methods, and that correct prediction of consequences remains a significant challenge (p. 18).
Applicant is reminded that generally, in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus (Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956 (Fed. Cir. 2002); Noelle v. Lederman, 355 F.3d 1343 (Fed. Cir. 2004); Regents of the University of California v. Eli Lilly Co., 119 F.3d 1559 (Fed. Cir. 1997); AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ 1780, 1790 (Fed. Cir. 2014)). A patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017) at page 1358). An adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed” (See page 1117). See also, Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed” (See Vas-Cath at page 1116). A “mere wish or plan” to obtain the claimed invention is not sufficient (Centocor Orth Biotech, Inc. v. Abbott Labs, 636 F.3d 1341 (Fed. Cir. 2011); Regents of the Univ. of California, 119 F.3d at 1566). In the instant application, the skilled artisan cannot envision the detailed chemical structure of the genus of non-natural, modified NKG2D receptors, wherein the receptors bind non-natural, modified α1-α2 domains of NKG2D ligands (but not natural ligands), and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The receptors are required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Therefore, a non-natural, modified human NKG2D receptor that binds non-natural, modified α1-α2 domains of NKG2D ligands (but not natural ligands), wherein said receptor comprises a human NKG2D ectodomain and an intracellular costimulatory domain and does not comprise an active CD3-zeta domain, wherein said receptor comprises mutations at amino acid positions 152 and/or 199 of a human NKG2D ectodomain, and wherein the amino acid at position 152 is replaced with alanine, serine, threonine, or valine and the amino acid at position 199 is replaced with phenylalanine, but not the full breadth of the claims meets the written description provision of 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. § 112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115). See also Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1355 (Fed. Cir. 2010).
Claim Rejections - 35 USC § 112(a)
6. Claims 8-11 are 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 non-natural, modified human NKG2D receptor on a mammalian cell that binds non-natural, modified α1-α2 domains of NKG2D ligands (but not natural ligands), wherein said receptor comprises a human NKG2D ectodomain and an intracellular costimulatory domain and does not comprise an active CD3-zeta domain, wherein said receptor comprises mutations at amino acid positions 152 and/or 199 of the human NKG2D ectodomain, and wherein the amino acid at position 152 is replaced with alanine, serine, threonine, or valine and the amino acid at position 199 is replaced with phenylalanine, does not reasonably provide enablement for a non-natural, modified NKG2D receptor attached to a mammalian cell wherein a costimulatory domain is attached intracellularly to the modified NKG2D receptor without the presence the presence of an active CD3-zeta domain, wherein the receptor binds non-natural, modified α1-α2 domains of NKG2D ligands but not natural ligands of NKG2D. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Claim 8, for example, is directed to a non-natural, modified NKG2D receptor attached to a mammalian cell wherein a costimulatory domain is attached intracellularly to the modified NKG2D receptor without the presence the presence of an active CD3-zeta domain, wherein the receptor binds non-natural, modified α1-α2 domains of NKG2D ligands but not natural ligands of NKG2D.
The specification of the instant application teaches that non-natural NKG2D receptors have been mutated at one or two specific sites, each of which results in compromised or loss of binding to all natural α1-α2 domains of NKG2D ligands (page 12, [0035]). The specification continues to disclose that the instant invention creates CARs (chimeric antigen receptors) that when attached to a mammalian cell surface provide a silenced receptor that serves as a surrogate high affinity receptor for the attachment to the cell surface of heterologous atoms or molecules (page 12, [0035]). The specification indicates that when the CD3-zeta domain of a direct activation-competent CAR is selectively inactivated, it can still act as a silent CAR and enable the cognate non-natural ligand-attached heterologous molecules that have defective binding to their respective natural receptor or receptor subunits to transmit signals to the cell via their respective other receptor subunits (page 13, [0037]; Example 8). The specification continues to teach that a functional costimulatory domain is required to enable a heterologous molecule to mediate its respective signal to the CAR cell (page 13, [0037-0038]; Example 8). The specification teaches the generation of three different NKG2D receptors with modified ectodomains: “Y152”; “Y199”; and “Y152/Y199” (double mutant) (pages 20-22, Example 1; Figure 1A). The specification also indicates that single amino acid substitutions are explored at residues 152 and 199 (page 21, [0059]). Alanine, serine, threonine, and valine do not impact assembly of the Fc-NKG2D molecule, although leucine results in highly aggregated material (pages 21-22, [0059]; Figure 18). Additionally, alanine, glutamate, and aspartate are not tolerated at position 199 (page 22, [0059]; Figure 18). The specification concludes that of the combinations of mutations explored, Y152A/Y199F, Y152S/Y199F, Y152T/Y199F, and Y152F/Y199F do not negatively impact dimer formation, whereas other combinations resulted in increased aggregation (page 22, [0059]). Further experiments in the specification indicate that single mutant NKG2D candidates have diminished binding of natural ligand, ULBP2 (page 25, [0066]; Figure 20) while all double mutant candidates (Y152A/Y199F; Y152S/Y199F; Y152T/Y199F; Y152V/Y199F) have eliminated to significantly reduced binding (page 25, [0066-0067]; Figures 19-20).
It is noted that the instant specification does not provide a specific definition for a non-natural or modified NKG2D receptor and thus, the phrase is broadly interpreted by the Examiner as reading upon any NKG2D receptor that binds non-natural α1-α2 domains of NKG2D ligands (but not natural ligands). Therefore, the claims encompass an infinite number of NKG2D receptors with any number of modifications. However, the specification does not teach any non-natural, modified NKG2D receptor attached to a mammalian cell with the limitations recited in instant claims 8-11, other than a human NKG2D receptor comprising mutations at amino acid positions 152 and/or 199, wherein the amino acid at position 152 is replaced with alanine, serine, threonine, or valine and the amino acid at position 199 is replaced with phenylalanine.
The problem of predicting protein and DNA structure from sequence data and in turn utilizing predicted structural determinations to ascertain functional aspects of the protein and DNA is extremely complex. While it is known that many amino acid substitutions are generally possible in any given protein the positions within the protein's sequence where such amino acid substitutions can be made with a reasonable expectation of success are limited. Certain positions in the sequence are critical to the protein's structure/function relationship, e.g. such as various sites or regions directly involved in binding, activity and in providing the correct three-dimensional spatial orientation of binding and active sites. These or other regions may also be critical determinants of antigenicity. These regions can tolerate only relatively conservative substitutions or no substitutions (see Wells, 1990, Biochemistry 29:8509-8517; Ngo et al., 1994, The Protein Folding Problem and Tertiary Structure Prediction, pp. 492-495). However, Applicant has provided little or no guidance beyond the mere presentation of sequence data to enable one of ordinary skill in the art to determine, without undue experimentation, the positions in a NKG2D receptor (other than amino acids 152 and 199) which are tolerant to change (e.g. such as by amino acid substitutions or deletions), and the nature and extent of changes that can be made in these positions. Even if an active or binding site were identified in the specification, they may not be sufficient, as the ordinary artisan would immediately recognize that an active or binding site must assume the proper three-dimensional configuration to be active, which conformation is dependent upon surrounding residues; therefore substitution of non-essential residues can often destroy activity. The art recognizes that function cannot be predicted from structure alone (Bork, 2000, Genome Research 10:398-400; Skolnick et al., 2000, Trends in Biotech. 18(1):34-39, especially p. 36 at Box 2; Doerks et al., 1998, Trends in Genetics 14:248-250; Smith et al., 1997, Nature Biotechnology 15:1222-1223; Brenner, 1999, Trends in Genetics 15:132-133; Bork et al., 1996, Trends in Genetics 12:425-427). See also Tokuriki et al. (Current Opinion in Structural Biology 19: 596-604, 2009), who teach that mutations are generally destabilizing. For instance, Tokuriki et al. teach at page 596, right column, last paragraph, that “as mutations accumulate, protein fitness declines exponentially...or even more than exponentially...So by the time an average protein accumulates, on average, five mutations, its fitness will decline to <20%.” Further, at page 598, left column, last paragraph, Tokuriki et al. note that 50% of mutations are destabilizing, and >15% of mutations are highly destabilizing, and of the about 5% of mutations that are stabilizing values...many of these mutations result in inactive protein. Indeed, Tokuriki et al. conclude that “a more comprehensive understanding of how mutations affect protein fitness within living cells is needed, including their combined effects on function, thermodynamic and kinetic stability, and clearance through aggregation and degradation” (see page 602, left column, 2nd paragraph). Fenton et al. (Medicinal Chemistry Research 29:1133-1146, 2020) also state that while it is well known that most substitutions at conserved amino acid positions (which they call “toggle” switches) abolish function, it is also true that substitutions at nonconserved positions (which they call “rheostat” positions) are equally capable of affecting protein function. They conclude that substitutions at rheostat positions have highly unpredictable outcomes on the activities and specificities of protein-based drugs. Bhattacharya et al. (PLoS ONE 12(3): e0171355, 2017) state that the range of possible effects of even single nucleotide variations at the protein level are significantly greater than currently assumed by existing software prediction methods, and that correct prediction of consequences remains a significant challenge (p. 18). Furthermore, when multiple mutations are introduced, there is even less predictability. For evidence thereof, see Guo et al. (PNAS USA 101(25):9205-10, 2004), who state that the effects of mutations on protein function are largely additive (page 9207, left column, full paragraph 2). Fenton et al. supra, also acknowledge this (see abstract). Regarding NKG2D receptors, the state of the art teaches that amino acid substitutions Y199A and Y152A/Y199A in human NKG2D result in the loss of binding of both natural and non-natural α1-α2 domain ligands (Landgraf et al. US 2018/0134765, page 13, [0091]). Culpepper et al. (Mol Immunol 48: 516-5423, 2011) disclose that mutations Y152F and Y152I of human NKG2D actually increase receptor affinity to natural ligand, MICA (page 519, column 1, 1st paragraph; Table 1). Thus, the substitution of even a single amino acid alters the ligand binding characteristics of the modified NKG2D receptor and there is little guidance in the specification indicating which amino acids/regions are considered essential for the NKG2D receptor to retain the desired activities of the instant claims.
The amount of experimentation required to generate a genus of non-natural, modified NKG2D receptors that that bind non-natural, modified α1-α2 domains of NKG2D ligands (but not natural ligands) would not have been routine, much less could one of ordinary skill in the art predict that any one or combination of modifications (such as substitutions, insertions, deletions or post-translational modifications) encompassed by the instant claims would result in a functional non-natural, modified NKG2D receptor. Because of this lack of guidance in the instant specification, the extended experimentation that would be required to determine which modifications would be acceptable to retain occluding structural and functional activity, and the fact that the relationship between the sequence of a protein/peptide and its tertiary structure (i.e. its activity) are not well understood and are not predictable, it would require an undue amount of experimentation for one of skill in the art to arrive at the large number of non-natural, modified NKG2D receptors that bind non-natural, modified α1-α2 domains of NKG2D ligands (but not natural ligands) of the encompassed claims. Applicant has not provided sufficient guidance to enable one of ordinary skill in the art to make and use the genus of genus of non-natural, modified NKG2D receptors that bind non-natural, modified α1-α2 domains of NKG2D ligands (but not natural ligands) in the claims in a manner reasonably correlated with the scope of the claims. The scope of the claims must bear a reasonable correlation with the scope of enablement. See In re Fisher, 166 USPQ 19 24 (CCPA 1970).
Due to the large quantity of experimentation necessary to generate non-natural, modified NKG2D receptors that bind non-natural, modified α1-α2 domains of NKG2D ligands (but not natural ligands) and screen such for the desired functional activity; the lack of direction/guidance presented in the specification regarding the same; the absence of working examples directed to the same; the complex nature of the invention; the state of the prior art which establishes the unpredictability of the effects of mutation on protein structure and function; and the breadth of the claims, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
7. Claims 8-11 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No. 11,957,714. Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are directed to a non-natural, modified NKG2D receptor attached to a mammalian cell wherein a costimulatory domain is attached intracellularly to the modified receptor without the presence of an active CD3-zeta domain.
Claim 8 of the instant application recites a non-natural, modified NKG2D receptor attached to a mammalian cell wherein a costimulatory domain is attached intracellularly to the modified NKG2D receptor without the presence the presence of an active CD3-zeta domain, wherein the receptor binds non-natural, modified α1-α2 domains of NKG2D ligands but not natural ligands of NKG2D.
Meanwhile, claim 1 of the ‘714 patent recites a non-natural, modified NKG2D receptor comprising a human NKG2D ectodomain that comprises a substitution at position 152 selected from alanine, serine, threonine or valine and/or a substitution at residue 199 which is phenylalanine, wherein the receptor is attached to a mammalian cell, and wherein the receptor binds to non-natural, modified α1-α2 domains of NKG2D ligands but not to natural ligands of NKG2D, and wherein the modified NKG2D receptor does not comprise an active CD3-zeta intracellular signaling domain and does not activate intracellular signaling in the mammalian cell upon formation of an immunological synapse. Claim 2 of the ‘714 patent recites that the modified NKG2D receptor further comprises a costimulatory domain.
The non-natural, modified NKG2D receptor of the ‘714 claims comprises the same elements of the instant claims (a non-natural, modified NKG2D receptor that binds to non-natural, modified α1-α2 domains of NKG2D ligands but not to natural ligands of NKG2D; and a modified NKG2D receptor that further comprises a costimulatory domain, but does not comprise an active CD3-zeta intracellular signaling domain). Therefore, the non-natural, modified NKG2D receptor claims of the ‘714 patent are species claims that anticipate the genus claims of the instant application.
Conclusion
No claims are allowable.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Li et al. Human Cell Stem Cell 23: 181-192, 2018 (teach the construction of a NK-CAR comprising the transmembrane domain of NKG2D; a costimulatory domain; and a CD3zeta domain comprising point mutations (page 183, column 1; Figure 2A, “CAR4(meso)CD3Δ” and “CAR4(meso)ALLΔ”); do not teach that the receptor binds non-natural, modified NKG2D ligands because the extracellular domain of NKG2D is not utilized in the constructs)
Love et al. Cold Spring Harbor Perspect Biol 2: a002485, 2010 (review of the role of ITAM sequences in the CD3 domain)
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRIDGET E BUNNER whose telephone number is (571)272-0881. The examiner can normally be reached Monday-Friday 9:00 am-6:00 pm.
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, Joanne Hama can be reached at (571) 272-2911. 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.
BEB
Art Unit 1647
07 August 2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647
Prosecution Insights