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 .
DETAILED ACTION
1. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 3/3/26 has been entered.
Applicant’s amendment and response filed 3/3/26 is acknowledged and has been entered.
2. Applicant is reminded of Applicant's election without traverse of Group I and species of Notch agonist that is immobilized delta-like proteins, transduced naïve T cells, CAR and the method steps recited in claim 30 in Applicant’s amendment and response filed 1/28/25. Applicant is reminded that upon consideration of the prior art, examination had been extended to Jagged-1 and Jagged-2.
Claims 1, 2, 5, 6, 9, 12, 14, 23, 26, 29-33, 47 and 48 are presently being examined as they read upon the elected species (Delta Like ligands 1, 3 and 4) and also on Jagged-1 and Jagged-2, with the said species corresponding to one of SEQ ID NO: 11-17. Instant claim 1 is an independent claim.
3. 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.
4. Claims 1, 2, 5, 6, 9, 12, 14, 23, 26 and 29-33 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. This is a written description rejection.
Applicant has broadly claimed:
a method of culturing a naïve T cell (TN) in vitro, the method comprising exposing a native T cell to a medium comprising a Notch receptor agonist for a time sufficient to induce Notch receptor signaling in the cell
“wherein the Notch receptor agonist is selected from a polypeptide comprising an amino acid sequence with at least 85% (about 80%...99%) sequence identity” to the sequence set forth in SEQ ID NO: 11, 12, 13, 14, 15 16 or 17,
wherein the Notch receptor agonist binds in a region corresponding to (i) amino acid position 1 to about amino acid position 1446 of SEQ ID NO: 7; (ii) amino acid position 1 to about amino acid position 1421 of SEQ ID NO: 8; (iii) amino acid position 1 to about amino acid position 1382 of SEQ ID NO: 9; or (iv) amino acid position 1 to about amino acid position 1170 of SEQ ID NO: 10, and wherein the Notch receptor agonist is immobilized on a surface or a scaffold, wherein the surface is not a cell surface, and wherein the TN cells or one or more progeny cells thereof after the exposure are T cells having the characteristics of CD62L+ and CD45RO- (as is recited in instant base claim 1); and
including wherein the Notch receptor agonist, upon binding to a Notch receptor, induces a conformational change of the Notch Receptor resulting in exposure of an S2 cleavage site in the negative regulatory region (NRR) of the Notch receptor (dependent claim 14).
As such, the Notch receptor agonist recited in the claimed method is partially structurally recited (wherein the % identity is less than 100% to a particular recited Notch ligand, i.e., % identity is less than 100% to one of SEQ ID NO: 11-17), as well as functionally recited (“Notch receptor agonist”), and including as to which region of particular Notch receptors they bind (that is, a regional receptor-binding specificity to one of the Notch receptors recited in instant base claim 1, i.e., to a partial sequence of one of SEQ ID NO: 7-10). As is explained in more detail below, the recited Notch receptor agonist must possess the functional properties of binding to the Notch receptor and thereafter inducing a conformational change of the Notch receptor resulting in exposure of an S2 cleavage site in the NRR of the Notch receptor and inducing Notch receptor signaling in a cell.
The Notch receptor may be one of SEQ ID NO:7 (human Notch 1 receptor), SEQ ID NO: 8 (human Notch 2 receptor), SEQ ID NO: 9 (human Notch 3 receptor), or SEQ ID NO: 10 (human Notch 4 receptor) (see paragraph spanning pages 29-30 of the instant specification and the sequence listing).
The specification discloses at page 25, lines 12-21 that SEQ ID NO: 11 is Jagged 1, SEQ ID NO: 12 is Jagged 2, SEQ ID NO: 13 and 14 are DLL1 proteins, SEQ ID NO: 15 and 16 are DLL3 proteins, and SEQ ID NO: 17 is DLL4.
A search of the GenBank Accession numbers that the specification associates with these sequences indicate that these sequences are human, i.e., SEQ ID NO: 11 (AAC51731, Jagged1), SEQ ID NO: 12 (AAD15562, Jagged2), SEQ ID NO: 13 (ABC26875, delta-like 1, partial), SEQ ID NO: 14 (NP005609, delta-like protein 1 precursor), SEQ ID NO: 15 (NP_982353.1, delta-like protein 3 isoform 2 precursor), SEQ ID NO: 16 (NP_058637.1, delta-like protein 3 isoform 1 precursor), and SEQ ID NO: 17 (NP_061947.1, delta-like protein 4 precursor).
The recitation of the Notch receptor agonist [polypeptide] used in the claimed method by partial structure and function as well as by a binding specificity to the ECD (extracellular domain) of one of four recited Notch receptors in a broad region of each said Notch receptor does not provide adequate written description.
As a side issue, as is discussed in more detail below, the degree of partial structure recited in instant base claim 1 is broader than the recitation of “at least 85%” sequence identity. This is because the recitation in instant base claim 1 of “wherein the Notch receptor agonist is selected from a polypeptide comprising an amino acid sequence with at least 85% (about 80%....and 99%) sequence identity to the sequence set forth in SEQ ID NO: 11, 12, 13, 14, 15, 16 or 17” is indefinite, i.e., the polypeptide must comprise an amino acid sequence with at least 85% amino acid sequence identity to one of SEQ ID NO: 11-17, but according to the limitations recited in the parenthetical “()”, the polypeptide must also comprise an amino acid sequence with at least about 80%-99% sequence identity to one of the said SEQ ID NO: 11-17. The lower ranges recited in the parentheses are lower than at least 85%. The specification discloses “The word “about” indicates a number within range of minor variation above or below the stated reference number. For example, “about” can refer to a number within a range of 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% above or below the indicated reference number” (see page 53 at lines 25-28). According to the specification, the range can include a difference of 10% or less; however, this 10% difference is exemplary, not limiting. So for instance, applying the exemplary at least 10% difference to the numerical values recited in the parentheses at either end of the range translates to 72% amino acid sequence identity for the limitation “about 80%”, and 80% amino acid sequence identity for the limitation “about 99%”, all values that are lower than the “at least 85%” limitation recited before the parentheses.
Neither does the recitation of where a Notch receptor agonist binds to one of the recited Notch receptor proteins, nor the recited variants of the agonists, provide the fully defined structure of the said agonist that is used in the claimed method. It is clear that the genus of such Notch receptor agonists recited in the claims is much broader than the species disclosed in the instant specification.
The specification does not disclose a representative number of species of such Notch receptor agonists used in the claimed method, nor sufficient relevant identifying characteristics in the form of structure or functional characteristics coupled with a known or disclosed correlation between structure and function.
An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Amer. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by "whatever characteristics sufficiently distinguish it"). "Compliance with the written description requirement is essentially a fact-based inquiry that will ‘necessarily vary depending on the nature of the invention claimed.' " Enzo Biochem, 323 F.3d at 963, 63 USPQ2d at 1612. An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. See MPEP 2163 I.A.
An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613 (quoting the Written Description Guidelines, 66 Fed. Reg. at 1106, n. 49, stating that "if the art has established a strong correlation between structure and function, one skilled in the art would be able to predict with a reasonable degree of confidence the structure of the claimed invention from a recitation of its function".). "Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function." See MPEP 2163 II.3.
A “Notch receptor agonist” must possess the functional properties of binding to the Notch receptor and thereafter inducing a conformational change of the Notch receptor resulting in exposure of an S2 cleavage site in the NRR of the Notch receptor and inducing Notch receptor signaling in a cell. The specification discloses that a Notch receptor agonist not only binds to the extracellular domain of a Notch receptor, but binds in a manner that applies sufficient force, or “tug”, to induce the conformational change required to expose the S2 cleavage site, thereby inducing Notch receptor signaling in a cell (i.e., agonist activity). The specification discloses that the Notch receptor agonist must be appropriately presented to the cell expressing the Notch receptor in order to achieve this “tug” (see below).
The specification disclose on page 24 at lines 1-9 that the term “Notch receptor agonist” is a molecule that specifically binds to a Notch receptor in a manner that functionally results in Notch signaling when the Notch receptor is expressed on the surface of a cell, e.g., a ligand that binds to a mammalian Notch 1, 2, 3 or 4 receptor or an affinity reagent that specifically binds to a Notch receptor, and that has agonist functionality resulting in Notch receptor signaling in the cell expressing the Notch receptor. The Notch receptor agonist can also [be] referred to generally as a Notch ligand, Notch agonist, Notch receptor agonist ligand, “and the like.”
The specification further discloses that as used herein, the term “Notch signaling” or other references to the function of Notch receptor when contacted with a Notch receptor agonist refers to the cell-signaling cascade that occurs from the proteolytic cleavage of the expressed mature Notch receptors in a cell membrane…As indicated, Notch signaling is initiated by proteolytic cleavage at an S2 site near the C-terminal end of the ECD. In a resting or non-signaling state the S2 cleavage site is protected by a closed conformation of the negative regulatory region (NRR), which directly occludes the cleavage site and prevents access to the protease (page 24 at lines 10-19). The specification discloses the ligand-mediated activation of signaling occurs when the ligand binds to the ECD in a manner resulting in a conformational change that exposes the S2 cleavage site in the NRR of the ECD. The conformational change is not necessarily automatic, but occurs when the ligand or other binding molecule imposes a force or strain on the Notch receptor such that the closed conformation of the NRR is altered. Accordingly, a Notch receptor agonist not only binds to the ECD, but binds in a manner that applies sufficient force, or “tug”, to induce the conformational change required to expose the S2 cleavage site. The functionality of a “tug” in any Notch ligand or binding molecule can be accomplished by appropriately presenting the Notch receptor agonist to the cell expressing the Notch receptor (page 24 at lines 20-31).
The specification discloses that the agonist affinity reagents bind Notch with agonist functionality when they bind to the Notch ECD (extracellular domain) without interfering with the functionality of the negative regulatory region (NRR) to undergo a conformational change and that the domain in the Notch ECD available for binding to confer signaling capability extends generally from the N-terminus to just before the beginning of the NRR. The specification further discloses that in some embodiments the agonists should bind to particular epitopes for Notch 1, 2, 3 or 4.
The specification disclose that canonical Notch ligands in mammals included Delta proteins (e.g., DLL1,DLL3, or DLL4) or Jagged proteins (e.g., Jagged1 and Jagged2) (page 25 at lines 7-19). The specification discloses that the canonical Notch ligands, collectively referred to as DSL ligands, typically contain an N-terminal region, a DSL domain, and at least two EGF-like repeats, which are necessary for interaction with EGF repeats 11 and 12 of Notch receptors (page 25 at lines 21-26).
The specification discloses that a person of ordinary skill in the art can readily identify minimal Notch binding domains from known or putative Notch ligands (page 26 at lines 1-2). However, the Notch receptor agonists recited in the instant method claims is not confined to minimal contiguous portions of the known Notch receptor ligands and experimentation is not a rationale for providing adequate written description.
The specification discloses that the culturing of T cells in the presence of Notch agonist allows for quantitative signaling Notch pathway, and that signaling through Notch during culture of naïve T cells resulted in a less differentiated phenotype, as determined through observations of CD45RO, CD62L, costimulatory molecules (i.e., CD27 and CD28), and activation markers (i.e., PD-1, LAG-3 and CD69) (page 58 at lines 19-27).
As is stated above in this rejection, the functional recitation of an “agonist” that is also partially structurally recited, including with a recitation of the region where it binds to a particular Notch receptor, does not provide sufficient written description.
An additional issue is presented by dependent claim 12. Claim 12 recites “wherein the Notch receptor agonist comprises a domain of a mammalian Notch receptor ligand that binds to a mammalian Notch1,” ‘ 2, 3, or 4 receptor’, whereas instant base claim1 recites that the Notch receptor agonist is selected from a polypeptide having at least 85%...sequence identity to one of the human Notch receptors represented by SEQ ID NO: 11-17. There is no evidence of record for species of mammalian Notch receptor ligands that are at least 85% identical or about 80% identical to a human Notch receptor ligand that is one of SEQ ID NO: 11-17 and that binds to a mammalian Notch 1, 2, 3, or 4 receptor and also binds to a recited region of one of the human Notch receptors recited in base claim 1.
Therefore, it appears that the instant specification does not adequately disclose the breadth of the Notch receptor agonist used in the method recited in the instant claims. In light of this, a skilled artisan would reasonably conclude that Applicant was not in possession of the genus of all such Notch receptor agonists, and hence was not in possession of the method that uses them at the time the instant application was filed.
Applicant’s arguments have been fully considered but are not persuasive. Applicant’s said arguments are of record in the amendment and response filed 3/3/26 on pages 13-15.
Applicant argues that claim 1 is limited to a structurally defined subset of agonists that are based on expressly disclosed sequences (SEQ ID NOs: 11-17), retain a conserved structural motif identified in the specification, bind a specifically mapped epitope on a Notch receptor, and exhibit the desired Notch signaling. Applicant points to paragraphs in the pgPUB of the instant specification US20210292711A1 (“See for example, paragraphs [0062], [0063], [0090], [0091] and [0093]-[0098] and Example 1.”) Applicant reproduces paragraph [0093] that discloses that canonical Notch ligands (or DSL ligands) typically contain an N-terminal region, a DSL domain, and at least two EGF-like repeats which are necessary for interaction with EGF repeats 11 and 12 of Notch receptors. The said paragraph also cites an NPL that teaches a 2.3 angstrom resolution crystal structure of interacting regions of Notch1 receptor with DLL4 ligand, indicating structural components of this ligand-receptor complex important for binding, as well as some modifications to the wild type DLL4 that enhances binding affinity to the receptor. Applicant further argues that the application discloses SEQ ID NOs: 11-17, identifies the core structural motifs of the agonists, the residues required for receptor interaction, positions amenable to substitutions without compromising binding and demonstrates Notch signaling upon binding of the claimed agonists. Applicant asserts that because of this, the claims satisfy the written description requirement.
However, Applicant’s said arguments are not persuasive for the following reasons.
The teaching of a crystal structure of interacting regions of Notch1 receptor with a DLL4 ligand and binding enhancing modifications does not provide for the identity of the wild-type amino acid residues and their variant amino acid substituents that can be changed and not negatively affect ligand receptor binding and signaling. In the said NPL reference cited in the instant specification (i.e., Luca et al., 2015, 347: 847-853), the study was performed with yeast-displayed DLL4 (one that consisted of the N terminus plus EGFs 3-5) and Notch 1 receptor tetramers (i.e., soluble Notch 1 receptor tetramers) because yeasts do not encode for the O-glycosylation enzymes required for modification of Notch EGFs and because this receptor-ligand pair represent the mammalian pair with the highest intrinsic affinity. The said reference teaches that Notch receptor/ligand interactions are dependent upon posttranslational modification of Notch receptors with O-glucose and O-fucose and influence signaling activity, factors that were clearly not addressed in the cited reference. The said reference also teaches that DLL3 has only 6 out of 15 Notch1-binding residues that are conserved, and that DLL3 has been reported not to bind or activate Notch (i.e., DLL3 that are represented by SEQ ID NO: 15 and 16 that are recited in the instant claims are each a different DLL3 protein). The said reference teaches two affinity-enhanced mutants of DLL4, one of which has specific amino acid residue substituents at one of three positions, whereas the other has particular substitutions at seven positions (three of which are the same as in the first variant). The sequence of DLL4 corresponding to instantly recited SEQ ID NO: 17 is 1218 amino acid residues in length. 85% identity to SEQ ID NO: 17 constitutes 1158 residues that must be identical and 60 that can be different. It is clear even for SEQ ID NO: 17, that two affinity matured variants of DLL4 comprising 3 substitutions or 7 substitutions taught by Luca et al. falls far short of 60 possible substitutions and does not address changes in EGF3-8 that may potentially affect the conformation of the entire protein or the aforementioned different posttranslational modifications that can affect agonist activity through their effect on signaling. Point-in-case, the said reference teaches that none of the substituted amino acid residues in the three-amino acid substituted variant directly contact Notch 1, but rather probably strengthen the interaction by stabilizing a particular hinge or adjacent area of DLL4, while only two substituted residues out of seven in the second variant occur at DLL4 contact positions in the model (first paragraph on page 852). It is also important to note that other amino acid substitutions at those particular positions were tested experimentally and found not to enhance binding affinity (not tested for abrogation of binding; no testing for agonist activity). Experimentation would be required to determine which amino acid substitutions aside from those combinations of three or seven positions and their particular amino acid residue substituents are permissive for the functional properties of binding to a Notch receptor and possessing agonist activity through binding affinity, inducing a conformational change of the Notch receptor resulting in exposure of an S2 cleavage site in the NRR of the Notch receptor, and inducing Notch receptor signaling in a cell even for DLL4.
Note that a comparison of sequence identity of SEQ ID NO: 17 (NP_061947.1, delta-like protein 4 precursor, DLL4 that is addressed in Luca et al.) against each of SEQ ID NOs: 11-16 reveals very low sequence identity (as well as low sequence similarity) (see evidentiary reference Emboss Needle comparison for SEQ ID NO: 17 (DLL4) with each of SEQ ID NO: 11-16)*:
SEQ ID NO % identity*
SEQ ID NO: 11 (Genbank Acc. No. AAC51731, Jagged1) 19.3%
SEQ ID NO: 12 (Genbank Acc. No. AAD15562, Jagged2) 20.2%
SEQ ID NO: 13 (Genbank Acc. No. ABC26875, delta-like 1, partial) 11.2,%
SEQ ID NO: 14 (Genbank Acc. No. NP005609, delta-like protein 1 precursor) 48.5%
SEQ ID NO: 15 (Genbank Acc. No.NP_982353.1, delta-like protein 3 isoform 2 precursor) 31.0%
SEQ ID NO: 16 (Genbank Acc. No.NP_058637.1, delta-like protein 3 isoform 1 precursor) 31.6%
*(see evidentiary references (file names) “EMBOSS_output_SEQ_ID_NO_17 vs” 11, 12, 13, 14, 15 and 16 for the percent identity listed above).
Second and more importantly, there is no recitation in the claims that the DSL domain and the EGF-like repeats are not modified. Even if this were not so and there was such a recitation, there is no disclosure as to which non-DSL domain/EGF-like repeats residues may be modified and what they may be modified to in order to preserve the correct conformation and functioning of the agonist to bind to the receptor and activate it.
The specification does not identify positions amenable to substitutions and what amino acid substitutions will not compromise the functional properties of binding and signaling. For these reasons and those enunciated in the instant rejection, Applicant has not provided adequate written description.
5. 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.
6. Claims 1, 2, 5, 6, 9, 12, 14, 23, 26, 29-33, 47 and 48 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.
a) Claim 1 is indefinite in the recitation of “wherein the Notch receptor agonist is selected from a polypeptide comprising an amino acid sequence with at least 85% (about 80%....and 99%) sequence identity to the sequence set forth in SEQ ID NO: 11, 12, 13, 14, 15, 16 or 17” because it is not clear what is meant, i.e., the polypeptide must comprise an amino acid sequence with at least 85% amino acid sequence identity to one of SEQ ID NO: 11-17, but according to the limitations recited in the parenthetical, the polypeptide must also comprise an amino acid sequence with at least about 80%-99% sequence identity to one of the said SEQ ID NO: 11-17. First of all, the lower ranges recited in the parentheses are lower than at least 85%. Secondly, the instant specification discloses “The word “about” indicates a number within range of minor variation above or below the stated reference number. For example, “about” can refer to a number within a range of 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% above or below the indicated reference number” (see page 53 at lines 25-28). According to the specification, the range can include a difference of 10% or less; however, this 10% difference is exemplary, not a limiting definition. So applying at least the 10% difference to the numerical values recited in the parentheses at either end of the range translates to 72% amino acid sequence identity for the limitation “about 80%” and 80% amino acid sequence identity for the limitation “about 99%, all values that are lower than the “at least 85%” limitation recited before the parentheses.
b) It bears repeating that as is stated above in part “a)”, the limitation “about” when applied to the amino acid sequence identities as well as to the position number ranges appearing in instant base claim 1 is also indefinite because of the lack of a limiting definition for about based upon “a number within range of minor variation” above or below the stated reference number.
c) Claim 6 is also indefinite in the recitation of “at least about 12 hours” because it is not clear what is meant in the absence of a limiting definition for about based upon “a number within range of minor variation” above or below the stated reference number.
d) Claim 9 is indefinite in the recitation of “less than about 50%” because it is not clear what is meant in the absence of a limiting definition for about based upon “a number within range of minor variation” above or below the stated reference number.
e) Claim 23 is indefinite in the recitation of “about 0.01 ug/ml to about 100 ug/ml” because it is not clear what is meant in the absence of a limiting definition for about based upon “a number within range of minor variation” above or below the stated reference number.
f) Claim 30 is indefinite in the recitation of “at least about 40% of the population of TN cells” because it is not clear what is meant in the absence of a limiting definition for “about” based upon “a number within range of minor variation” above or below the stated reference number.
g) A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
Claim 30 recites the broad recitation of its instant base claim 1, i.e., “and wherein the TN cells or one or more progeny cells thereof after the exposure are T cells having the characteristics of CD62L+ and CD45RO-“, and the claim also recites “and at least about 40% of the population of the TN cells or one or more progeny cells thereof after the exposure are T cells having the characteristics of CD62L+ and CD45RO-“ which is the narrower statement of the range/limitation. In instant base claim 1, all of the TN cells must have the CD62L marker and lack the CD45RO marker, but in claim 30 only about 40% of the population of the TN cells need have the said phenotype. In addition the limitation “about” before 40% is indefinite for the reasons stated above, i.e., the lack of a limiting definition therefore.
h) Claim 26 is indefinite in the recitation of “in an effective concentration that modulates TN differentiation” because it is not clear what is meant in the absence of a limiting definition for “modulates” in the instant specification. The common art definition of “modulates” is ‘acting as an activator, an inhibitor, or both’ or of ‘adjusting or regulating the degree of’’**, therefore the modulation of differentiation can be up or down. This said limitation is indefinite in view of the newly recited limitation in instant base claim 1 of “wherein the TN cells or one or more progeny cells thereof after the exposure are T cells having the characteristics of CD62L+ and CD45RO-“, which the specification discloses as discloses is a naïve, less differentiated phenotype, as well as in view of the limitation that all of the TN cells or one or more progeny cells thereof have the said characteristics of CD62L+ and CD45RO-“, but the rest need not (see page 82 at lines 5-8 of the instant specification. It is not clear which cytokines or biologically active fragments thereof or combinations thereof 2will maintain the less undifferentiated phenotype. **(See evidentiary reference The Free Dictionary (www.thefreedictionary.com/modulate, 2026, 1 page) for the definition of modulate.
7. 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.
8. 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 broader limitations than does its base claim. Claim 12 recites “wherein the Notch receptor agonist is selected from a polypeptide comprising an amino acid sequence with at least 85%...sequence identity to the sequence set forth in SEQ ID NO: 11, 12, 13, 14, 15, 16 or 17” (which are human Notch ligands, see specification at 25, lines 12-19 and evidentiary references with file name starting with “EMBOSS_output…” that are cited above in this office action) and “wherein the agonists binds to an extracellular domain of a notch receptor…..” that is one of a human Notch 1-4 receptor (see specification at page 23, lines 11-25) through its dependence on instant base claim 1, and the claim also recites “wherein the Notch receptor agonist comprises a domain of a mammalian Notch receptor ligand that binds to a mammalian Notch1, Notch2, Notch3, or Notch4 receptor”. A mammalian Notch receptor ligand and a mammalian Notch receptor ligand are both broader than a human Notch receptor and Notch receptor ligand.
Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
9. Applicant’s amendment filed 3/3/26 has overcome the prior rejection of record of claims 1, 2, 5, 6, 9, 12, 14, 26, 29-30 and 48 under 35 U.S.C. 103 as being unpatentable over US2018/119100 A1 (IDS reference) in view of Liu et al.(J. Cell. Biochem., 2017, 118: 785-796, of record).
Applicant has amended the claims to recite SEQ ID NO: 11 (amongst other sequences) which the instant specification discloses (at page 25, line 14) to be Jagged 1 having GenBank Accession No. AAC51731, a limitation the art references do not teach. A search of the associated GenBank Accession number for SEQ ID NO: 11 (AAC51731, Jagged1), indicates that this sequence is a human Jagged 1 sequence. The primary art reference US2018/119100 A1 discloses a human Jagged 1 sequence having the sequence corresponding to SEQ ID NO: 61 therein. However, the said art reference sequence does not meet the present claim limitations as explained below.
Instantly recited SEQ ID NO: 11 is 1218 amino acid residues in length, whereas SEQ ID NO: 61 of the art reference is 838 amino acid residues in length. A comparison of instantly recited SEQ ID NO: 11 with SEQ ID NO: 61 of the art reference reveals 29.0% identity. Thus, the art sequence SEQ ID NO: 61 does not comprise an amino acid sequence with at least 85% sequence identity to instantly recited SEQ ID NO: 11 The limitation newly recited in instant base claim 1). The recitation of at least 85% identity to SEQ ID NO: 11 requires that 1158 amino acid residues must be identical, but only 296 residues of SEQ ID NO: 61 of the art reference are identical to those found in instantly recited SEQ IDNO: 11)(100% identity from residues 1-296 of SEQ ID NO: 11 with residues 23-318 of SEQ ID NO: 61 of the primary art reference). The art reference also teaches a homo sapiens Jagged 1 corresponding to SEQ ID NO: 63 of the art reference that appears to be a subsequence of SEQ ID NO: 61 of the art reference. As such it also does not meet the present claim limitations.
For completeness of the record however, Applicant’s argument ----that there is allegedly no prima facie case of obviousness because the combined references fail to teach or suggest all elements of the claims and one of ordinary skill in the art would not be motivated to combine the cited art because said combination would frustrate the purpose of the primary art refence (expanding Tregs)—is not persuasive. This is because the primary art reference discloses that Notch 3 mediated signaling sustains the regulatory phenotype of Tregs ([0047]), increases Treg numbers ([0045]), and that Notch 3 is preferentially expressed on Tregs ([0040], [0114]). Although the art references do not explicitly teach the limitation recited in instant base claim 1 “wherein the [cultured] TN cells or one or more progeny cells thereof have the characteristics of CD62L+ and CD45RO-“ (which the instant specification discloses is a naïve, less differentiated phenotype, see page 82 at lines 5-8 of the instant specification), the naïve T cell is a Treg that is being exposed to a medium comprising Jagged 1, so the cell phenotype must necessarily be the same as is recited in instant base claim 1. (In the prior rejection of record, the combined references teach the same method step using the same ingredient when referring to Jagged 1 in general, and exclusive of SEQ ID NO: 11 that is presently recited in base claim 1.) It does not appear that the claim language or limitations result in a manipulative difference in the method steps when compared to the prior art disclosure. See Bristol-Myers Squibb Company v. Ben Venue Laboratories 58 USPQ2d 1508 (CAFC 2001). “{i}t is a general rule that merely discovering and claiming a new benefit of an old process cannot render the process again patentable.” In re Woodruff, 16 USPQ2d 1934, 1936 (Fed. Cir. 1990). Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 201 USPQ 658 (CCPA 1979). Granting a patent on the discovery of an unknown but inherent function would remove from the public that which is in the public domain by virtue of its inclusion in, or obviousness from, the prior art. In re Baxter Travenol Labs, 21 USPQ2d 1281 (Fed. Cir. 1991). See M.P.E.P. 2145.
With further regard to Applicant’s further argument that the secondary art reference teaches immobilizing Notch ligand to beads for the purpose of circumventing cell proliferation, and the allegation that this would defeat the purpose of the primary art reference which is proliferating T cells, Applicant is mischaracterizing the said reference, as the cells expressing the Jagged 1 or DLL4 (“Notch ligand-expressing cells”) were treated with Mitomycin C in order to prevent (Jagged 1- or DLL-4- expressing-) cell proliferation during co-culture, not for circumventing proliferation of the T cells. (See Liu et al. at page 787, column 2 at the first full paragraph, i.e., “proliferation of Notch ligand cells”, that is, cells expressing Notch ligand Jagged 1). Notably, Liu et al. teach that Notch ligands immobilized on beads mimicked the cell-surface Notch ligand activity expressed by cells and that the bead-based method could be widely adopted and used as an alternative to the co-culture system, providing cells for cell therapy (e.g., conclusion section).
10. Applicant’s amendment filed 3/3/26 has overcome the prior rejection of record of claims 23 and 31-33 under 35 U.S.C. 103 as being unpatentable over US2018/119100 A1 (IDS reference) in view of Liu et al.(J. Cell. Biochem., 2017, 118: 785-796) as applied to claims 1, 2, 5, 6, 9, 12, 14, 26, 29-30 and 48 above, and further in view of Hull et al.(J. Autoimmunity, 2017, 79: 63-73) for the reasons of record stated above. In addition, Applicant is arguing Hull et al. separately.
11. Applicant’s amendment filed 3/3/26 has overcome the prior rejection of record of claims 1, 2, 5, 6, 9, 12, 14, 23, 26, 29-30, 47 and 48 under 35 U.S.C. 103 as being unpatentable over US2018/119100 A1 (IDS reference) in view of Liu et al.(J. Cell. Biochem., 2017, 118: 785-796) and Dallman et al.(Curr. Opin. Immunol., 2005, 17: 259-266, of record) for the reasons of record stated above. In addition, Applicant is arguing Dallman et al. separately.
12. Applicant’s amendment filed 3/3/26 has overcome the prior rejection of record of claims 31-33 under 35 U.S.C. 103 as being unpatentable over US2018/119100 A1 (IDS reference) in view of Liu et al.(J. Cell. Biochem., 2017, 118: 785-796) and Dallman et al.(Curr. Opin. Immunol., 2005, 17: 259-266, of record), as applied to claims 1, 2, 5, 6, 9, 12, 14, 23, 26, 29-30, 47 and 48 above, and further in view of Hull et al.(J. Autoimmunity, 2017, 79: 63-73) for the reasons of record stated above. In addition, Applicant is arguing Hull et al. and Dallman et al. separately.
13. For the purpose of prior art rejections, the filing date of the instant claims is deemed to be the filing date of PCT/US2019/048574, i.e., 8/28/2019, as provisional application serial no. 62/723,936 does not support the claimed limitations of the instant application. The said provisional application does not provide support for SEQ ID NO: 11-17, the percentage of the TN cells in the population changes after the exposing by less than about 50% (claim 9), for IL-6, IL-21, IL-23, TBFb (claim 26), or for at least about 40% of the population of the TN cells or one or more progeny cells thereof after the exposure are T cells having the characteristics of CD62L+ and CD45RO- (claim 30).
Applicant’s arguments in the amendment and response filed 3/3/26 (of record on pages 9-11 at section “IV”) pertaining to the date for the purpose of prior art rejections have been considered but are not persuasive.
The provisional application does not provide support for SEQ ID NO: 11-17 (corresponding to forms of human Jagged 1, Jagged 2, DLL3, DLL4, and/or DLL5) (and note for example that there is evidence in the prosecution record that there can be different sequences that are termed Jagged 1, such as SEQ ID NO: 11 of the instant application or SEQ ID NO: 61 of prior art reference US2018/119100 A1(of record); there may also be different isoforms or variants of Jagged 1, Jagged 2, DLL3, DLL4, and/or DLL5). Regarding Applicant’s arguments that Figures 61 and 6B provide support for instant dependent claim 9, said argument is not persuasive, as the said Figures only consider the DLL1 ligand and do not address the issue of the limitation appearing in claim 9 of “less than about” 50%, as the limitation “about” is indefinite as is enunciated above in this office action; regarding Applicant’s argument pertaining to claim 26, neither do the cited portions of the said provisional application specification nor claims 21 and 22 of said provisional application provide support for the species IL-6, IL-21, IL-23, TBFb; regarding Applicant’s argument pertaining to claim 30, example 1 and Figs 5A and 5B of the said provisional application only consider the DLL1 ligand, and thus do not provide support for the breadth of the limitations recited in the claim.
14. 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.
15. 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.
16. Claims 1, 2, 5, 6, 9, 12, 14, 23, 26, 29, 30 and 48 are rejected under 35 U.S.C. 103 as being unpatentable over US2018/119100 A1 (IDS reference) in view of Liu et al.(J. Cell. Biochem., 2017, 118: 785-796, of record), Uniprot Acc. No. P78504 (2002, 14 pages) and De Rosa et al. (Nature Medicine, 2001, 7(2): 245-248), as evidenced by an admission in the specification on page 25 at lines 12-14.
Claim interpretation: The specification discloses that the word “about” indicates a number within range of minor variation above or below the stated reference number…for example, “about” can refer to a number within a range of 10% above or below the indicated reference number (page 53 at lines 25-28). The claims recite the open transitional phrase “comprising” opening the claims to encompass other ingredients and/or method steps. The specification discloses that DLL1, DLL3, DLL4, JAG1, JAG2 (i.e., Delta Like ligand, Jagged) are Notch receptor agonists (e.g., page 9 at lines 24-25, page 16 at lines 7-14). The specification discloses that binding of these agonist to the Notch receptor, a conformational change occurs that exposes an S2 cleavage sit in the NRR of the Notch receptor (e.g., page 16 at lines 18-20). As a limiting definition of “naïve T cell” is not disclosed in the specification, this limitation is being interpreted with the art known meaning as mature T cells that have not yet encountered their cognate antigens (for example, see evidentiary reference Badovinac and Harty (Microbes and Infection, 2002, 4:441-447, see especially section 2 at the first sentence, of record). The specification discloses at page 25, line 14 that SEQ ID NO: 11 is Jagged 1. A search of the associated GenBank Accession number SEQ ID NO: 11 (AAC51731, Jagged1), indicates that this sequence is human. The “wherein” clause recited in instant base claim 1, i.e., “wherein the TN cells or one or more progeny cells thereof after the exposure are T cells having the characteristics of CD62L+ and CD45RO-“, is being interpreted as being a phenotype that results from performing the active method step recited in said claim when starting with a population of Tregs comprising naïve TN cells or alternatively that results from starting with a population of naïve Tregs. The specification discloses that in some embodiments the population of TN cells comprises at least about 40% to about 100% of TN cells (page 3 at lines 24-30).
Instant base claim 1 recites:
Claim 1 (Currently amended) A method of culturing a naïve T (TN) cell in vitro, comprising exposing a native T (TN) cell to a medium comprising Notch receptor agonist for a time sufficient to induce Notch receptor signaling in the cell, wherein the Notch receptor agonist is selected from a polypeptide comprising an amino acid sequence with at least 85% (about 80%....and 99%) sequence identity to the sequence set forth in SEQ ID NO: 11, 12, 13, 14, 15, 16 or 17, wherein the agonist binds to an extracellular domain of a notch receptor in a region corresponding to (i) amino acid position 1 to about amino acid position 1446 of SEQ ID NO: 7; (ii) amino acid position 1 to about amino acid position 1421 of SEQ ID NO: 8; (iii) amino acid position 1 to about amino acid position 1383 of SEQ ID NO: 9; or (iv) amino acid position 1 to about amino acid position 1170 of SEQ ID NO: 10, and wherein the Notch receptor agonist is immobilized on a surface or a scaffold, wherein the surface is not a cell surface, and wherein the TN cells or one or more progeny cells thereof after the exposure are T cells having the characteristics of CD62L+ and CD45RO-.
US2018/119100 A1 discloses expanding (culturing) Treg cells using OX40L+Jagged-1+ bone marrow derived dendritic cell culture (i.e., immobilized or cell surface expressed Jagged-1) for 5 days. US2018/119100 A1 discloses that Notch 3 is preferentially expressed on Tregs. US2018/119100 A1 discloses that the culturing may also be with soluble Jagged-1 and soluble OX40L, as well as adding in IL-2. US2018/119100 A1 discloses that the ex-vivo cultured cells may be isolated. US2018/119100 A1 discloses that Notch 3 mediated signaling sustains the regulatory phenotype of Tregs ([0047]), increases Treg numbers ([0045]), and that Notch 3 is preferentially expressed on Tregs ([0040], [0114]) (and this extends to Tregs when they are isolated after culturing step). US2018/119100 A1 discloses that expanding Tregs facilitates their use in administering the Tregs as a treatment for autoimmune diseases. US2018/119100 A1 exemplifies use of naïve T cells (see entire reference, especially abstract, [0006], [0033],[0040], [0042], [0052], [0077], [0079], claims 1 and 3).
US2018/119100 A1 does not disclose that the Jagged-1 is immobilized on a surface or scaffold that is not a cell surface in the culturing method, nor that the Jagged 1 has the sequence of instantly recited SEQ ID NO: 11.
Liu et al. teach that immobilized Notch ligand on beads is equivalent to that immobilized on a cell surface when inducing Notch activity (wherein the Notch ligand is JAG1 (Jagged 1) and wherein the level of activation was the same using either full length JAG1 or a truncated version comprised of the N-terminus through the EGF3 domain (e.g., abstract, Figure 2A (depicting full length JAG1 with 16 EGF-like domains), page 789 at column 1, at the middle paragraph, Figure 5C). Liu et al. teach that use of Notch ligand-presenting cells in co-culturing systems (such as in the method disclosed by the primary art reference that uses Notch ligand expressing cells) has drawbacks (e.g., page at column 1 at the first full paragraph). Liu et al. teach that their method for immobilizing Notch ligand proteins to microbeads is simple, and offers a convenient way to stimulate cells in culture in vitro, including those intended for cell therapy. Liu et al. teach that their bead-based method could be widely adopted and used as an alternative to the cell co-culture system (especially last paragraph). Liu et al. teach culturing the JAG1 beads with cells resulted in peak NOTCH receptor activation between approximately 8-12 hours (e.g., Fig. 3). Although Liu et al. teach using full length JAG1, they do not teach the amino acid sequence of full length JAG1. See entire reference.
Uniprot Acc. No. P78504 discloses the full length sequence of Jagged 1 (Table appearing in the “Family & Domains”, “Features” section, showing 16 EGF-like domains) (that is identical to instantly recited SEQ ID NO: 11) and that the GenBank Accession No. associated with this entry is AAC5173.1 (see “Sequence databases” section at the first entry). See entire reference.
The admission in the specification on page 25 at lines 12-14 is that SEQ ID NO: 11 is Jagged 1 associated with GenBank Accession No. AAC5173.1.
De Rosa et al. teach that naïve T cells are those that have been released by the thymus into circulation, but have not yet encountered their cognate antigens (paragraph spanning columns 1-2 on page 245). De Rosa et al. teach using lack of expression of CD45RO (i.e., CD45RO-) and an additional marker such as CD62L (i.e., CD62L+) to distinguish naïve T cells from memory, but that other phenotypic markers for naïve cells include expression of CD27 and CD28, low or absent expression of activation markers such as CD44 and HLA-DR, and low expression of FAS receptor (CD95) (first full paragraph at column 2 on page 245). De Rosa et al. teach that naïve T cells have the most diverse TCR diversity (second full paragraph at column 2 on page 245). See entire reference.
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have used the beads taught by Liu et al. having a Notch ligand such as JAG1, including with OX40L additionally disposed thereon (or with OX40L on separate beads) in the method of culturing naïve T cells disclosed by the primary art reference in place of the cells expressing JAG1, including for 8-12 hours as taught by Liu et al. for their JAG1 beads. It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have used the full length JAG1 taught by Liu et al. having the sequence taught by Uniprot Acc. No. P78504 that is identical to instantly recited SEQ ID NO: 11. It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have isolated TN cells having the CD45RO-/CD62L+ or the expanded phenotype that have the highest degree of TCR diversity taught by De Rosa et al. after culturing the population of Tregs or to have isolated the said TN having the said phenotype before and after the culturing step.
One of ordinary skill in the art would have been motivated to do this in order to reap the advantages of using a stimulator-cell-free co-culture system as taught by Liu et al in proliferating the TN cells having high TCR diversity to sufficient numbers for subsequent therapeutic administration as is disclosed by the primary art reference.
Although the art references do not recite that the Notch ligand binds in the region of SEQ ID NO: 9 (i.e., Notch receptor 3) that is recited in instant base claim 1, the primary art reference does discloses that Notch 3 is preferentially expressed on Tregs, and the recited range of amino acids (i.e., “amino acid position 1 to about amino acid position 1383 of SEQ ID NO: 9”) comprises the area that plays a role in ligand interaction (see sentence spanning pages 15-16 of the instant specification).
With regard to the limitation “naïve T cell” or “TN“, the instant claims are being included in this rejection because Treg cells are a population that comprises a subpopulation of naïve T cells and because the primary art reference exemplifies use of naïve T cells.
Instant dependent claim 6 is included in this rejection because Liu et al. teach peak activation of Notch receptor between 8-12 hours using their JAG1 beads, and also because the recited culturing time of “at least 12 hours” is a result effective variable that is within the purview of one of ordinary skill in the art to determine. Instant dependent claim 23 is included in this rejection because the concentration of JAG1 is a result effective variable that is within the purview of one of ordinary skill in the art to determine.
Instant dependent claims 9 and 30 are included in this rejection because the primary art reference also discloses that the culturing with Jagged-1+ caused selective proliferation of Tregs without activating T effector cells (i.e., “Teff”, those cells that have encountered their cognate antigens) (see [0042]), and therefore the percentage of naïve T cells in the population is expected to increase with culturing. In addition, De Rosa et al. teach that naïve T cells have the most diverse TCR diversity and it is desirable to use them, as is enunciated in the instant rejection.
Instant dependent claim 14 is included in this rejection because the instant specification discloses that the binding of an appropriate ligand to the Notch receptor results in a conformational change that exposes an S2 cleavage site in the NRR of the Notch receptor (see page 16 at lines 18-20).
Additionally, even if De Rosa et al. had not explicitly teach the limitation recited in instant base claim 1 “wherein the [cultured] TN cells or one or more progeny cells thereof have the characteristics of CD62L+ and CD45RO-“ (which the instant specification discloses is a naïve, less differentiated phenotype, see page 82 at lines 5-8 of the instant specification), the naïve T cell is a Treg that is being exposed to a medium comprising Jagged 1, so the phenotype must necessarily be the same as is recited in instant base claim 1. Although the art references do not teach the additional phenotypes recited in dependent claim 5, it does not appear that the claim language or limitations result in a manipulative difference in the method steps when compared to the prior art disclosure. See Bristol-Myers Squibb Company v. Ben Venue Laboratories 58 USPQ2d 1508 (CAFC 2001). “{i}t is a general rule that merely discovering and claiming a new benefit of an old process cannot render the process again patentable.” In re Woodruff, 16 USPQ2d 1934, 1936 (Fed. Cir. 1990). Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 201 USPQ 658 (CCPA 1979). Granting a patent on the discovery of an unknown but inherent function would remove from the public that which is in the public domain by virtue of its inclusion in, or obviousness from, the prior art. In re Baxter Travenol Labs, 21 USPQ2d 1281 (Fed. Cir. 1991). See M.P.E.P. 2145. (If this is not the case, the claims are missing critical limitations.) Therefore, the claimed method appears to be similar to the method of the prior art absent a showing of unobvious differences. Since the Patent Office does not have the facilities for examining and comparing the method of the instant invention to those of the prior art, the burden is on Applicant to show an unobvious distinction between the method of the instant invention and that of the prior art. See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977).
Although this is a new ground of rejection, Applicant is directed to the Examiner’s rebuttal of Applicant’s arguments directed towards the first two cited references in the present rejection (see item #7 above).
17. Claims 31-33 are rejected under 35 U.S.C. 103 as being unpatentable over
US2018/119100 A1 (IDS reference) in view of Liu et al.(J. Cell. Biochem., 2017, 118: 785-796, of record), Uniprot Acc. No. P78504 (2002, 14 pages) and De Rosa et al. (Nature Medicine, 2001, 7(2): 245-248), as evidenced by an admission in the specification on page 25 at lines 12-14, as applied to claims 1, 2, 5, 6, 9, 12, 14, 23, 26, 29, 30 and 48 above, and further in view of Hull et al.(J. Autoimmunity, 2017, 79: 63-73, of record).
Claim interpretation: The specification discloses that the word “about” indicates a number within range of minor variation above or below the stated reference number…for example, “about” can refer to a number within a range of 10% above or below the indicated reference number (page 53 at lines 25-28). The claims recite the open transitional phrase “comprising” opening the claims to encompass other ingredients and/or method steps. The specification discloses that DLL1, DLL3, DLL4, JAG1, JAG2 (i.e., Delta Like ligand, Jagged) are Notch receptor agonists (e.g., page 9 at lines 24-25, page 16 at lines 7-14). The specification discloses that binding of these agonist to the Notch receptor, a conformational change occurs that exposes an S2 cleavage sit in the NRR of the Notch receptor (e.g., page 16 at lines 18-20). As a limiting definition of “naïve T cell” is not disclosed in the specification, this limitation is being interpreted with the art known meaning as mature T cells that have not yet encountered their cognate antigens (for example, see evidentiary reference Badovinac and Harty (Microbes and Infection, 2002, 4:441-447, see especially section 2 at the first sentence, of record). The specification discloses at page 25, line 14 that SEQ ID NO: 11 is Jagged 1. A search of the associated GenBank Accession number SEQ ID NO: 11 (AAC51731, Jagged1), indicates that this sequence is human. The “wherein” clause recited in instant base claim 1, i.e., “wherein the TN cells or one or more progeny cells thereof after the exposure are T cells having the characteristics of CD62L+ and CD45RO-“, is being interpreted as being a phenotype that results from performing the active method step recited in said claim when starting with a population of Tregs comprising naïve TN cells or alternatively that results from starting with a population of naïve Tregs. The specification discloses that in some embodiments the population of TN cells comprises at least about 40% to about 100% of TN cells (page 3 at lines 24-30).
Instant base claim 1 recites:
Claim 1 (Currently amended) A method of culturing a naïve T (TN) cell in vitro, comprising exposing a native T (TN) cell to a medium comprising Notch receptor agonist for a time sufficient to induce Notch receptor signaling in the cell, wherein the Notch receptor agonist is selected from a polypeptide comprising an amino acid sequence with at least 85% (about 80%....and 99%) sequence identity to the sequence set forth in SEQ ID NO: 11, 12, 13, 14, 15, 16 or 17, wherein the agonist binds to an extracellular domain of a notch receptor in a region corresponding to (i) amino acid position 1 to about amino acid position 1446 of SEQ ID NO: 7; (ii) amino acid position 1 to about amino acid position 1421 of SEQ ID NO: 8; (iii) amino acid position 1 to about amino acid position 1383 of SEQ ID NO: 9; or (iv) amino acid position 1 to about amino acid position 1170 of SEQ ID NO: 10, and wherein the Notch receptor agonist is immobilized on a surface or a scaffold, wherein the surface is not a cell surface, and wherein the TN cells or one or more progeny cells thereof after the exposure are T cells having the characteristics of CD62L+ and CD45RO-.
US2018/119100 A1 in view of Liu et al., Uniprot Acc. No. P78504 (2002, 14 pages), and De Rosa et al., as evidenced by an admission in the specification on page 25 at lines 12-14, has been discussed above, hereafter referred to the “combined references”.
The combined references do not disclose that the method further comprises transducing the TN or the one or more progeny cells thereof with a heterologous nucleic acid molecule comprising a sequence that encodes an immune receptor that is a TCR that specifically binds to a peptide of interest bound to a MHC molecule.
Hull et al. teach transducing polyclonal Tregs with a TCR specific for a complex of an autoantigenic peptide/MHC, whereby use of these TCR-transduced cells resulted in endowment of cognate antigen specific responses and enabling antigen-specific suppression at increased potency as compared to that induced by polyclonal Tregs. Hull et al. teach further optimization of such TCRs for therapy (see entire reference, especially abstract, section 1 at column 1 on page 64, and conclusions section).
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have transduced the expanded Tregs of the combined references with a TCR such as one taught by Hull et al.
One of ordinary skill in the art would have been motivated to do this, and with a reasonable expectation of success in doing so, in order to further optimize the Tregs for therapeutic applications, particularly given the teaching of Hull et al. that such transduced cells are superior to their non-transduced counterparts.
Instant claim 32 is included in this rejection because the art transduced TCR comprises an extracellular domain that specifically binds to an antigen of interest (i.e., it binds to a cognate peptide/MHC complex) and is operatively linked to an intracellular domain that activates the T cell upon binding of the extracellular domain to the antigen of interest.
The combined references do not disclose a concentration or range thereof that is recited in instant dependent claim 23, i.e., wherein the Notch receptor agonist is present at a concentration of about 0.01 ug/ml to about 100 ug/ml.
18. Claims 1 and 30 are objected to because of the following informalities: the “+” and “-“ signs following the receptor markers must be superscripted. Claim 30 is also objected to because the “N” in “TN” at the second line should be subscripted as ‘TN’.
Appropriate correction is required.
19. No claim is allowed.
20. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIANNE DIBRINO whose telephone number is (571)272-0842. The examiner can normally be reached on M, T, Th, F.
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, MISOOK YU can be reached on 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Marianne DiBrino/
Marianne DiBrino, Ph.D.
Patent Examiner
Group 1640
Technology Center 1600
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
Prosecution Insights