DETAILED ACTION
Examiner acknowledges receipt of the reply filed 11/12/2025, in response to the restriction requirement mailed 09/16/2025.
Claims 1, 6-18, 20, and 21 are pending. Claims 2-5 and 19 have been cancelled. Claim 21 is newly added. Claims 8-12, 14-16, and 18 are withdrawn from further consideration for the reasons set forth below.
Claims 1, 6, 7, 13, 17, 20, and 21 are being examined on the merits in this office action.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The filing receipt dated 8/06/2025 provides the following:
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Examiner Comment
The drawings and specification filed 8/6/2025- after the instant filing date of 2/14/2023- have not been entered. The drawings and specification filed 8/6/2025 are deemed to be new matter for the reasons set forth herein. Please refer to the file wrapper.
Election/Restrictions
Applicant’s election of Group I (claims 1, 6, 7, 13, 17, 20, and 21) without traverse in the reply filed on 11/12/2025 is acknowledged.
Claims 8-12, 14-16, and 18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/12/2025.
Applicant’s election of the following species without traverse in the reply filed on 11/12/2025 is acknowledged.
costimulatory polypeptide comprising part (i) of claim 1
4-1BBL ectodomain (SEQ ID NO:1)
trimerization domain (SEQ ID NO:7)
leader sequence (SEQ ID NO:17)
affinity tag (SEQ ID NO:19)
linker (SEQ ID NO:9)
Claims 1, 6, 7, 13, 17, 20, and 21 read on the elected species.
Specification
Please note, the specification has not been checked to the extent necessary to determine the presence of all possible error. Applicant's cooperation is required in correcting any errors of which applicant may become aware in the specification. MPEP § 608.01.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink 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. See specification at p. 51, ll. 20 and 23-24 (specification filed 02/14/2023).
Please refer to the file wrapper:
The specification filed 8/6/2025 is deemed to constitute new matter and has not been entered. As noted, the filing receipt dated 8/06/2025 indicates that the instant application is a PCT of PCT/EP2021/078841.
The supplemental specification filed 8/06/2025, refers to PCT/US2018/066337, different than the claimed priority application. The supplemental specification further STARTS at page 135 and refers to sequences that are NOT part of the sequence listing filed 02/14/2023.
The Sequence listing filed 02/14/2023 contains 155 sequences.
The supplemental specification filed 8/06/2025 refers to e.g., SEQ ID NOs: 1134, 1514, 1234, etc. (e.g., pp. 135-136, 149-150). Per the file wrapper, these pages correlate with pages 1-2, and 14-15. Thus, the Supplemental specification contains sequences that are not included in the Sequence listing of record.
Sequence Compliance
This application is objected to because the peptide sequences at least at pages 80, last line; 83, l. 10; 85, l. 21; Figs 1A, 2A, 3A, 4A, 5A, 6A, 8A, 14A, 15A, and 16A are not associated with a sequence identifier (a SEQ ID NO). All sequences longer than ten nucleotides or four amino acids referenced in the specification must include a SEQ ID NO and must be included in the Sequence Listing. See MPEP § 2421-2422. Applicant must amend the specification in response to this office action and must confirm that all peptide sequences of the specification are included in the sequence listing.
Examiner requests that the Applicants review the specification to confirm that all of the peptides, as required, comply with MPEP § 2421-2422.
Drawings
Please refer to the file wrapper. The drawings filed 8/6/2025 constitute new matter.
The drawings filed 2/14/2023 contain Fig 1-17. The figure legends in the specification filed 2/14/2023 disclose the corresponding figure legends.
In contrast, the supplemental drawings filed 8/6/2025 start at Fig 24-86, which are not part of the as-filed application.
Accordingly, the drawings filed 8/6/2025 constitute new matter and have not been entered.
Sequence Interpretation/Claim Interpretation
The Office interprets claims comprising SEQ ID NOs: in the following manner: “comprising an amino acid sequence of SEQ ID NO: 1” requires only a dipeptide or more within SEQ ID NO: 1, “comprising the amino acid sequence of SEQ ID NO: 1” requires the full-length sequence with 100% identity to SEQ ID NO: 1 with or without additional amino acids at any N-/C-terminal ends or additional nucleotides at 5' /3' ends, “consisting of an amino acid sequence of SEQ ID NO: 1” would encompass any sequence of two or more consecutive amino acids (dipeptide or more) fully contained within SEQ ID NO: 1, and “consisting of the amino acid sequence of SEQ ID NO: 1” would be limited to the sequence of the amino acids as specified by SEQ ID NO: 1, and nothing more or less; "an amino acid selected from the group consisting of SEQ ID NOs: 1, 2 and 3” is any sequence of two or more consecutive amino acids (dipeptide or more) fully contained within SEQ ID NO: 1, 2 or 3; and “the amino acid selected from the group consisting of SEQ ID NOs: 1, 2, and 3” requires the full-length sequence with 100% identity to SEQ ID NOs: 1, 2, or 3 and the same length as SEQ ID NOs: 1, 2, or 3.
Claim Objections
Claims 6, 7, 17, and 21 are objected to because of the following informalities:
Claim 6 should be amended to recite “SEQ ID NOs: 9 to 16;[[,]] or a sequence having at least 90%, 91[[ ]]% 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to any one of
Claim 7 should be amended to recite “a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77 and[[or]] 79; or a nucleic acid sequence having at least 70%, 71[[ ]]%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to any one of and[[or]] 79.
Claim 17 recites two distinct compositions. The claim should be separated into two separate claims:
17. A kit comprising the costimulatory polypeptide of claim 1, wherein the kit comprises further reagents.
New claim. A kit comprising an oncolytic virus expressing the costimulatory polypeptide of claim 1, wherein the kit comprises further reagents.
Claim 21 should be amended to recite: “SEQ ID NOs: 3 to 6, or any one of SEQ ID NOs: 3-6 .
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 6, 7, 13, 17, 20, and 21 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient” (MPEP § 2163).
A claimed genus may be satisfied through sufficient description of a representative number of species or disclosure of relevant, identifying characteristics such as functional characteristics coupled with a known or disclosed correlation between function and structure (MPEP § 2163(3)a(II)). The number of species that describe the genus must be adequate to describe the entire genus; if there is substantial variability, a large number of species must be described.
The analysis for adequate written description considers (a) actual reduction to practice, (b) disclosure of drawings or structural chemical formulas, (c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure, and (d) representative number of samples.
In the instant case, the claims recite a costimulatory polypeptide comprising at least three 4-1BBL ectodomains and at least one trimerization domain, wherein each 4-1BBL ectodomain comprises consists of a minimal Tumor Necrosis Factor (TNF) Homology Domain according to SEQ ID NO: 1, or a sequence having at least 92%, 93%, 94%, 95%, 96%,97%, 98% or 99% sequence identity to SEQ ID NO:1; wherein the trimerization domain is a human or humanized trimerization domain; wherein the polypeptide binds to 4-1BB on the surface of a 4-1BB expressing cell and thus triggers 4-1BB-mediated immune cell stimulation; and wherein the trimerization domain is selected from SEQ ID NO: 7 and SEQ ID NO: 8.
Claim 6 recites wherein the polypeptide comprises at least one linker individually selected from the group consisting of SEQ ID NOs:6-9, or a sequence having at least 90% identity thereto.
Claim 7 recites wherein the costimulatory peptide is encoded by a nucleic acid sequence selected from the group consisting of the recited SEQ ID NOs, or sequence having at least 70% identity thereto.
Claim 17 recites a kit comprising the costimulatory polypeptide, or an oncolytic virus expressing the costimulatory peptide of claim 1, wherein the kit comprises further reagents.
Claim 21 recites wherein the 4-1BBL ectodomain comprises or consists of a sequence according to SEQ ID NOs:3-6 or a sequence having at least 90% identity thereto.
As noted above, the claim term “comprises” is interpreted as reading on a full length amino acid sequence with 100% identity to SEQ ID NO:1, with or without additional amino acids at the N-/C- termini. The claim term “consists” is interpreted as reading on a minimum of two consecutive amino acid sequences [dipeptide] within SEQ ID NO:1. At a minimum, the claimed costimulatory polypeptides encompass 2 consecutive amino acids of SEQ ID NO:1, or at least 92% sequence identity thereto.
The issue at question is whether a person of ordinary skilled in the art would be able to determine what structural feature/amino acid sequence is required for the instant claimed costimulatory polypeptide to have sequence identity with SEQ ID NO: 1, and to have the functional characteristics of being able to bind 4-1BB and trigger 4-1BB mediated immune cell stimulation.
(a) actual reduction to practice and (b) disclosure of drawings or structural chemical formulas:
The specification reduced to practice 6 costimulatory polypeptides that comprised either 1 or 3 4-1BBL domains of either SEQ ID NOs: 1 or 4 (Ex 1, Table 1). The specification reduced to practice 2 trimerization domains – full-length SEQ ID NO:7 or 8 (see Table 1). The specification reduced to practice 4 linkers- full-length SEQ ID NOs: 9, 11, 12, and 15. See Table 1.
Of the claimed costimulatory polypeptides comprising three (3) 4-1BBL domains and a trimerization domain- only 1 costimulatory polypeptide was reduced practice, SEQ ID NO: 66. Instant SEQ ID NO:67 appears to the nucleic acid encoding the costimulatory polypeptide of instant SEQ ID NO:1.
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Instant SEQ ID NO:1 has 100% identity with amino acids 6-158 of instant SEQ ID NO:4 (which is 170 amino acids in length).
Thus, the specification only reduced to practice a single costimulatory polypeptide of the claimed invention comprising three 4-1BBL ectodomain [full-length instant SEQ ID NO:1] and a trimerization domain [full-length instant SEQ ID NO:7].
The specification does not describe a general correlation between structure and function for the claimed genus of costimulatory polypeptides comprising a 4-1BBL ectodomain comprising or consisting of SEQ ID NO: 1, or variants having 92% identity thereof, and further having the function of binding the 4-1BB receptor and triggering 4-1BB mediated immune cell stimulation.
(c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure:
As discussed above, in the instant case, based on the disclosure of instant specification, other than the limited examples, a person of ordinary skilled in the art would not be able to determine what structural feature is required for the claimed costimulatory polypeptides comprising a 4-1BBL ectodomain comprising or consisting of SEQ ID NO: 1, or variants having 92% identity thereof, and further having the function of binding the 4-1BB receptor and triggering 4-1BB mediated immune cell stimulation.
Furthermore, the present application is attempting to patent what has not yet been invented and the fact that one of skill in the art can test for the effect used to determine the compounds does not necessarily confer sufficient written description. The claimed peptide sequence would entail testing limitless potential peptides and proteins, and one of skill in the art could afterwards still be faced with no hits with the desired functionality.
In addition, it is well known in the peptide/protein art that even single amino acid changes or differences in the amino acid sequence of a protein can have dramatic effects on the protein’s function. As an example of the unpredictable effects of mutations on protein function, Drumm et al (Annu. Rev. Pathol. Mech. Dis., 2012, 7, pages 267-282) teach cystic fibrosis is an autosomal recessive disorder caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene, for example, page 268, Section “CYSTIC FIBROSIS”. Drumm et al further teach several mutations can cause cystic fibrosis, including two mutations G551D and G551S; and clinical consequences are quite different for these two changes, as the G551D variant has virtually no detectable activity, and consequently a classic, severe phenotype is associated; G551S, however, has reduced but clearly detectable function and is associated with a much milder presentation of CF, for example page 269, left column, the last paragraph. Drumm et al also teach that in the most common cystic fibrosis mutation ΔF508 (the absence of amino acid 508 of the normally 1,480-amino acid protein) gives rise to the cystic fibrosis phenotype, for example, page 268, right column, the 2nd paragraph. Thus, even the substitution or deletion of a single amino acid can have dramatic and unpredictable effects on the function of the protein. The unpredictability of the effect of amino acid substitution on the function and/or property of peptide/protein is further confirmed and discussed in Yampolsky et al (Genetics, 2005, 170, pages 1459-1472). Yampolsky et al teach even conservative substitution can significantly affect the function of the protein/peptide, for example, page 1465, Table 3. Although the disclosures of Drumm et al and Yampolsky et al are directed to proteins/peptides other than costimulatory polypeptides that comprise a 4-1BBL ectodomain, they illustrate the inherent unpredictability with respect to the biological activity of a given protein/peptide after even minor changes to the primary amino acid sequence.
Therefore, based on the state of art, a person of ordinary skilled in the art would not be able to determine what structural feature is required for the claimed costimulatory polypeptides comprising or consisting of SEQ ID NO: 1, or variants having 92% identity thereof, and further having the function of binding the 4-1BB receptor and triggering 4-1BB mediated immune cell stimulation.
(d) representative number of samples:
In the instant case, the genus of instant claimed polypeptide sequences recited encompasses numerous variants which may include any number of natural and unnatural amino acids. SEQ ID NO:1 is 153 amino acids in length. A sequence of 92% identity allows for 12 amino acid changes. This equates to 12 amino acids of any amino acid (20 naturally occurring amino acids) is 1220 or 3.83x1021 potential polypeptides. These numbers are actually significantly higher when one considers that the that amino acid changes can occur at any of the 153 amino acid positions within SEQ ID NO: 1, and further encompasses both naturally and unnaturally occurring amino acids. As noted above, the claim term “consists” is interpreted as reading on a minimum of two consecutive amino acid sequences [dipeptide] within SEQ ID NO:1. At a minimum, the costimulatory polypeptides encompass 2 consecutive amino acids of SEQ ID NO:1, or at least 92% sequence identity thereto in the 4-1BBL ectodomain.
Claim 7 recites nucleic acid SEQ ID NOs encoding a claim costimulatory polypeptide. For example, SEQ ID NO:67 encodes the polypeptide of SEQ ID NO:66. SEQ ID NO:67 is 1929 nucleotides in length. . A nucleic acid sequence of 70% identity allows for 578 base changes. This equates to 578 bases of any nucleotide (4 naturally occurring DNA nucleotides) is 5784 or 1.12x1011 potential polypeptides.
Examiner reiterates that only 1 costimulatory polypeptide comprising at least three 4-1BBL active domains and at least one trimerization domain was reduced practice; SEQ ID NO:66. The costimulatory polypeptide of SEQ ID NO: comprise full-length SEQ ID NO:1 (4-1BBL ectodomain), full-length trimerization domain (SEQ ID NOL7), and three linkers (SEQ ID NOs: 9, 11, and 12) (Table 1).
Considering the scope of the genus of instant claimed polypeptide sequence, the instant specification fails to provide sufficient examples to describe the entire genus of peptide sequence claimed. The skilled artisan cannot extrapolate to all iterations and combinations of sequences that fall within the instant claim scope based on a single costimulatory polypeptide that was reduced practice.
Taken all these together, considering the state of the art and the disclosure in instant specification, it is deemed that the instant specification fails to provide adequate written description for the claimed genus of costimulatory polypeptides comprising or consisting of SEQ ID NO: 1, or at least 92% identity thereof, and further having the function of binding to the 4-1 BB receptor; and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 6, 7, 13, 17, 20, and 21 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.
Claim 1 recites “wherein each 4-1BBL ectodomain comprises consists of a minimal Tumor Necrosis Factor (TNF) homology domain according to SEQ ID NO:1”. The metes and bounds of the claim are deemed to be indefinite. As noted above, the claim term “comprises” is interpreted as reading on a full length amino acid sequence with 100% identity to SEQ ID NO:1, with or without additional amino acids at the N-/C- termini. The claim term “consists” is interpreted as reading on a minimum of two consecutive amino acid sequences [dipeptide] within SEQ ID NO:1. The metes and bounds of the claim are deemed to be indefinite. It is unclear from the claim and the specification as to the identity of peptides that are 4-1BBL ectodomain peptides and comprises consists of SEQ ID NO:1.
Because claims 6, 7, 13, 17, 20, and 21 depend from indefinite claim 1 and do not clarify the point of confusion, they must also be rejected under 35 U.S.C. 112, second paragraph.
Claim 1 recites the limitation "the polypeptide" at line 10. There is insufficient antecedent basis for this limitation in the claim.
To overcome this rejection, the claim should be amended to recite “the costimulatory polypeptide”.
Claim 6 recites the limitation "the polypeptide" at lines 1-2. There is insufficient antecedent basis for this limitation in the claim. To overcome this rejection, the claim should be amended to recite “the costimulatory polypeptide”.
Further regarding claim 6, the metes and bounds of the claim are deemed to be indefinite. Claim 6 recites “The costimulatory polypeptide of claim 1, wherein the polypeptide comprises at least one linker, wherein the at least one linker is individually selected from the group consisting of SEQ ID NOs: 9 to 16, …, or a nucleic acid sequence encoding the same”. The claim recites that the claimed costimulatory polypeptide can comprise a linker [with recited SEQ ID NOs], or a nucleic acid. It is unclear as to how the costimulatory polypeptide [amino acids] can be comprise a nucleic acid (structurally and physically different compound). Examiner expressly notes that the claims recite costimulatory polypeptide, not a conjugate. Specifically, the claimed costimulatory polypeptide would require that the linker is also a peptide [amino acids]. In contrast, a conjugate [not claimed] would allow for the linker to comprise different physical matter, e.g., nucleic acid.
To overcome this rejection, examiner recommends that the last phrase of the claim be deleted. Applicant should draft a new claim that is limited to the nucleic acid sequence. For instance: The costimulatory polypeptide of claim 6, wherein the linker is encoded by a nucleic acid sequence [or similar claim language].
Regarding claim 7, certain recited SEQ ID NOs don’t have proper dependency from claim 1. Claim 1 recites a costimulatory polypeptide comprising at least three 4-1BBL ectodomain of SEQ ID NO:1 (at least 92% identity) and a trimerization domain of SEQ ID NO:7 or 8.
Per pp. 24-25 of the specification, sequence descriptions:
SEQ ID NOs: NOs: 47, 49, 51, 53, 55, 57, 59, 73, and 77 appear to have one (1) 4-1BBL ectodomains, not three (3) ectodomains, as required by the instant claims.
SEQ ID NOs: NOs: 61 and 63 have 3 4-1BBL ectodomains, but no trimerization domain, as required by the instant claims.
Only SEQ ID NOs:65, 67, 69, 71, 75, and 79 appear to encode costimulatory polypeptide consistent with instant claim 1.
Claim 13 recites two consecutive "and/or" statements, and this grammatical arrangement raises substantial and material concerns regarding what possible combinations are required or optional in the claim scope because it is prima facie unclear if subsequent "and/or" statements are nested within earlier "and/or" statements, or merely intended to provide four alternative possibilities, from which at least one must be true. Claim 13 further recites the alternative claim term “or” twice in the claim. Applicant should clarify the claim scope by redrafting claim 13 to remove consecutive or potentially nested "and/or" statements.
Claim 13 further recites “checkpoint modulator, particularly a checkpoint inhibitor”. Regarding claim 13, the phrase "particularly" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05.
Examiner recommends that applicant draft a new dependent claim- “wherein the checkpoint modulator comprises a checkpoint inhibitor”.
Claim 20 recites three consecutive "and/or" statements, and this grammatical arrangement raises substantial and material concerns regarding what possible combinations are required or optional in the claim scope because it is prima facie unclear if subsequent "and/or" statements are nested within earlier "and/or" statements, or merely intended to provide two alternative possibilities, from which at least one must be true. Applicant should clarify the claim scope by redrafting claim 20 to remove consecutive or potentially nested "and/or" statements.
Claim 20 further recites the phrase “at least one 1, 6, sequence”. It is unclear from the claims and specification as to what applicant intends by this claim term. Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The term is indefinite because the specification does not clearly redefine the term.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 6, 13, 17, 20, and 21 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Song et al (WO2014/138314- cited in IDS filed 2/14/2023).
Song et al teach a costimulatory polypeptide comprising the 41BBL ectodomain and the collagen XV trimerization domain. The trimer-41BBL-HER2-T-cell engager (SEQ ID NO:7) encodes an N-terminal trimerization region of collagen XV NCI domain (col) that will form a stable trimer [reads on 3 4-1BBL ectodomains] (e.g., paras. [0070]-[0072]; Ex 14, Figs 18-19; paras. [0171]). Amino acids 407-559 of SEQ ID NO:7 have 100% identity with instant SEQ ID NO:1. As indicated by the specification, instant SEQ ID NO:8 correlates with the collagen XV domain (p. 66, ll. 20-22; Sequence listing description SEQ ID NO:8). Example 14 teaches expression of the costimulatory polypeptides and activation of T cells [reads on triggers 4-1BB mediated immune cell stimulation]. See also Figs 19-20. Thus, the limitations of instant claim 1 are satisfied.
Regarding claim 6, the costimulatory polypeptide of Song et al. comprises a linker of instant SEQ ID NO:9 at amino acid positions 141-145 of SEQ ID NO:7. A linker of instant SEQ ID NO:11 correlates with amino acid positions 139-153 of SEQ ID NO:7.
Regarding claim 13, the costimulatory polypeptides of Song further include an antibody like molecule, single-chain variable fragment (scFV) (Ex 14, Figs 18-19).
Regarding claim 17, Song et al teach a kit comprising the costimulatory polypeptide or an oncolytic virus expressing the costimulatory polypeptide. The kits can further include additional medicaments (paras. [0122], [0131], [0139]-[0145]).
Regarding claim 20, the costimulatory polypeptides of Song further include an affinity tag, e.g. Her2-scFv (Ex 14, Figs 18-19).
Regarding claim 21, the costimulatory polypeptide of Song comprises instant SEQ ID NO:4 at amino acid positions 402-571 of SEQ ID NO:7.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1, 13, 17, 20, and 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Rabu et al (J Biol Chem 280:41472-41481 (2005)- cited in IDS filed 2/14/2023), and further in view of Song et al (WO2014/138314- cited in IDS filed 2/14/2023).
Rabu et al teach recombinant human trimeric CD137L (4-1BBL). The costimulatory polypeptide comprises three 4-1BBL ectodomains (chimeric protein forms a homotrimer) and an AviTag trimerization domain (abstract, methods, pp. 41474-41480, Figs 1, 3). The polypeptide binds to 4-1BB on the surface of a 4-1BB expressing cell and triggers immune cell stimulation (abstract, pp. 41474-41480). The 4-1BBL ectodomain of Rabu et al comprises SEQ ID NO:1 (Fig 1).
Rabu et al do not expressly teach or suggest a trimerization domain of collagen domain XVIII (SEQ ID NO:7) or collagen domain XV (SEQ ID NO:8).
Song et al teach a costimulatory polypeptide comprising the 41BBL ectodomain and the collagen XV trimerization domain. The trimer-41BBL-HER2-T-cell engager (SEQ ID NO:7) encodes an N-terminal trimerization region of collagen XV NCI domain (col) that will form a stable trimer [reads on 3 4-1BBL ectodomains] (e.g., paras. [0070]-[0072]; Ex 14, Figs 18-19; paras. [0171]). Amino acids 407-559 of SEQ ID NO:7 have 100% identity with instant SEQ ID NO:1. As indicated by the specification, instant SEQ ID NO:8 correlates with the collagen XV domain (p. 66, ll. 20-22; Sequence listing description SEQ ID NO:8). Example 14 teaches expression of the costimulatory polypeptides and activation of T cells [reads on triggers 4-1BB mediated immune cell stimulation]. See also Figs 19-20. Song et al further teach that the trimerization domain can be human collagen type XV NCI, collagen type I, collagen type II, collagen type III, collagen type IV, collagen type V, or collagen type XI (para. [0016]).
It would have been obvious to one of ordinary skill in the art to substitute the trimerization domain of the costimulatory polypeptide of Rabu et al with a humanized trimerization domain of Song et al. The U.S. Federal Circuit has explicitly stated that in order to make a prima facie case of obviousness, the suggestion and motivation to combine the references need not be explicitly stated in the text of the references. In DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 80 USPQ2d 1641 (Fed. Cir. 2006), the Court writes, “the suggestion test is not a rigid categorical rule. The motivation need not be found in the references sought to be combined, but may be found in any number of sources, including common knowledge, the prior art as a whole, or the nature of the problem itself. In re Dembiczak, 175 F.3d 994, 999 [50 USPQ2d 1614] (Fed. Cir. 1999). As we explained in Motorola, Inc. v. Interdigital Tech. Corp., 121 F.3d 1461, 1472 [43 USPQ2d 1481] (Fed. Cir. 1997), ‘there is no requirement that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.’” See Dystar at 1645. “Our suggestion test is in actuality quite flexible and not only permits, but requires, consideration of common knowledge and common sense.” See Dystar at 1650. See also In re Fout, 675 F.2d 297, 301 (CCPA 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious.”). In this case, costimulatory polypeptides comprising a 4-1BBL ectodomain and a trimerization domain were known in the art at the time of the invention (as taught by Rabu et al and Song et al), so the motivation to substitute trimerization domains can be found in the common knowledge of the art and common sense of its skilled practitioners.
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting the Avitag trimerization domain of Rabu et al for a Collagen trimerization domain e.g., collagen domain XV, of Song et al because the cited references taught that the peptide domains were both trimerization domains. Therefore, these compositions are functional equivalents in the art, and substituting one for the other would have been obvious at the time of the invention. “When a patent ‘simply arranges old elements with each performing the same function it had been known to perform’ and yields no more than one would expect from such an arrangement, the combination is obvious.” See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) at 1395-1396, quoting Sakraida v. AG Pro, Inc., 425 U.S. 273 (1976) and In re Fout, 675 F.2d 297, 301 (CCPA 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious”). The rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395; Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969).
Accordingly, claim 1 is rendered obvious.
Regarding claim 13, Rabu et al teach the costimulatory polypeptides in HBS-EP buffer [construed as him pharmaceutically acceptable carrier]. Regarding claim 17, the claim term “kit” is not expressly defined in the specification. Rabu et al teach methods of preparing costimulatory polypeptides comprising 4-1BBL ectodomains, and a trimerization domain. The reference further teaches cell assays assessing T cell stimulation/activation. The components used in the cell assays of Rabu et al, comprising the costimulatory polypeptide, can be construed as a kit. Song et al teach a kit comprising the costimulatory polypeptide or an oncolytic virus expressing the costimulatory polypeptide. The kits can further include additional medicaments (paras. [0122], [0131], [0139]-[0145]). Regarding claim 20, the Avitag allows for biotin relation of the peptide which can then interact with streptavidin [reads on affinity tag] (Rabu et al at , e.g., abstract, methods, pp. 41477-8, Fig 1). Regarding claim 21, the costimulatory polypeptide of Rabu et al comprises the 4-1BBL ectodomain of SEQ ID NO:4 (Fig 1).
Claims 1, 13, 17, 20, and 21 obvious in view the teachings of the cited references.
Conclusion
No claims are allowed.
Claims 1, 6-18, 20, and 21 are pending. Claims 8-12, 14-16, and 18 are withdrawn.
Claims 1, 6, 7, 13, 17, 20, and 21 are rejected.
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/KRISTINA M HELLMAN/Examiner, Art Unit 1654