DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1-21 are pending. Claims 9-21 are withdrawn and claims 1-8 are presently examined.
Power of Attorney Not of Record
A POA has not been filed in the instant case (see Filing receipts mailed on 5/23/2023, 5/23/2023, 7/13/2023, 8/03/2023). Applicant is advised that in the absence of a POA, Examiner will be unable to conduct interviews or contact the Applicant if allowable subject matter is identified during prosecution.
Examiner Note
In the response to the Restriction Requirement, Applicant refers to the instant Application as a CIP (see Reply filed 12/29/2025 at p. 2 at § Priority) rather than a CON.
Per MPEP 211.02(a), “applicants are advised that only the benefit claims that are listed on the filing receipt have been recognized by the Office”. The filing receipts mailed on 5/23/2023, 5/23/2023, 7/13/2023, 8/03/2023 each identify the instant Application as a “CON of 17/181,884” under “Domestic Applications for which benefit is claimed”.
If desired, Applicant may file for a corrected filing receipt (see, e.g., MPEP § 211.02(a)). Per MPEP 211.02(a)(I), the corrected filing receipt will identify any deficiencies that may be present in the corrected ADS.
Election/Restrictions
Applicant’s election of Group I (peptide products, original claims 1-8, 12-16, and 21) and the species of SEQ ID NO: 27 in the reply filed on 12/29/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
The originally elected species is understood to be an Anti-PDL1 sdAb- human STINGΔTM fusion protein consisting of the sequence of SEQ ID NO: 27:
MGHHHHHHDYDIPTTENLYFQGSDYKDDDDKQVQLVETGGGLVQPGGSLRLSCTASGFTFSMHAMTWYRQAPGKQRELVAVITSHGDRANYTDSVRGRFTISRDNTKNMVYLQMNSLKPEDTAVYYCNVPRYDSWGQGTQVTVSSGGLPETGGLAPAEISAVCEKGNFNVAHGLAWSYYIGYLRLILPELQARIRTYNQHYNNLLRGAVSQRLYILLPLDCGVPDNLSMADPNIRFLDKLPQQTGDRAGIKDRVYSNSIYELLENGQRAGTCVLEYATPLQTLFAMSQYSQAGFSREDRLEQAKLFCRTLEDILADAPESQNNCRLIAYQEPADDSSFSLSQEVLRHLRQEEKEEVTVGSLKTSAVPSTSTMSQEPELLISGMEKPLPLRTDFS
The bolded sequence corresponds to an Anti-PDL11 sdAD and comprises instant SEQ ID NO: 72; the highlighted portion corresponds to a human STINGΔTM and comprises SEQ ID NO: 43; and the underlined portion is identified as optional (see, e.g., Spec. filed 5/04/2023 at SEQ ID NO: 27 at page 12, sequence listing noting that positions 1-31 are optionally absent). Applicant failed to identify if the optional portion was present or absent in the originally elected species, and therefore SEQ ID NO:27 with and without positions 1-31 are understood to be patentably indistinguishable obvious variants of one another.
Although Applicant alleges that this species reads upon claims 1-8, 12-16, and 21, this appears to be incorrect. Instant claims 12-16 require a “STING agonist”, which was not identified as present, and such embodiments are not identified as obvious variants of the species of SEQ ID NO: 27. Instant claim 21 requires a cell penetrating peptide, and no cell penetrating peptide within SEQ ID NO: 27 has been identified on record, and such embodiments are not identified as obvious variants of the species of SEQ ID NO: 27. Accordingly, the originally elected species only reads upon instant claims 1-8.
Following extensive search and consideration, the originally elected species has been deemed obvious in view of the prior art, as applied below. Per MPEP § 803.02(III)(A),
Following election, the Markush claim will be examined fully with respect to the elected species and further to the extent necessary to determine patentability. Note that where a claim reads on multiple species, only one species needs to be taught or suggested by the prior art in order for the claim to be anticipated or rendered obvious...
If the Markush claim is not allowable, the provisional election will be given effect and examination will be limited to the Markush claim and claims to the elected species, with claims drawn to species patentably distinct from the elected species held withdrawn from further consideration.
Accordingly, claims 1-8 are rejected in view of the originally elected species and claims that do not read upon the originally elected species are withdrawn.
Claims 9-11 and 17-20 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 12/29/2025.
Claims 12-16 and 21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/29/2025.
Claims 1-8 are presently considered.
Information Disclosure Statement
The IDS filed 5/17/2023 (9 pages), 5/17/2023 (7 pages); and 5/17/2023 (8 pages) are acknowledged.
Applicant should note that some documents disclosed on the IDS form filed 5/17/2023 (9 pages), 5/17/2023 (7 pages), and 5/17/2023 (8 pages) were not considered since they did not conform to 37 CFR 1.98(b) by providing a proper date, as 37 CFR 1.98(b) requires that each publication must be identified by publisher, author (if any), title, relevant pages of the publication, and date and place of publication. The date of publication supplied must include at least the month and year of publication, except that the year of publication (without the month) will be accepted if the applicant points out in the information disclosure statement that the year of publication is sufficiently earlier than the effective U.S. filing date and any foreign priority date so that the particular month of publication is not in issue. See MPEP 609.04(a). Here, the earliest claimed priority document is US Provisional Application 62/979,733, filed 2/21/2020; therefore, all publications published in or after 2019 must be accompanied by both a month and year of publication. References that were not considered have been indicated by strike-though on the attached IDS forms.
Denial of Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed applications, US Provisional Application 62/979,733 (filed 2/21/2020) and US Application 17/181,884 (filed 2/22/2021) each fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
Here, it is the Examiner’s understanding that the priority documents materially differ from the instant Application because Applicant has alleged that the instant Application was intended to be a CIP of the parent Application (see Reply filed 12/29/2025 at p. 2 at § Priority).
Legal Basis
Guidance for determining whether or not a priority document provides written description support for pending claims is addressed at MPEP § 2163.02, which explains that
If a claim is amended to include subject matter, limitations, or terminology not present in the application as filed, involving a departure from, addition to, or deletion from the disclosure of the application as filed, the examiner should conclude that the claimed subject matter is not described in that application.
This is pertinent because a written description analysis includes consideration of express, implicit, and inherent support (see MPEP § 2163), wherein “support” constitutes a description that “clearly allow[s] persons of ordinary skill in the art [to] recognize that he or she invented what is claimed” and to establish “that the inventor had possession at that time of the later claimed subject matter” (see, e.g., MPEP § 2163.02). A proper analysis includes consideration of claim scope and interpretation of terms (see, e.g., MPEP § 2163(I)(B), explaining that the written description requirement “serves to prevent an applicant from adding information that goes beyond the subject matter originally filed” and noting that “[n]ew or amended claims which introduce elements or limitations that are not supported by the as-filed disclosure violate the written description requirement”). This is consistent with MPEP § 2163(II)(1)-(2), which addresses generic terms and explains that “Each claim must be separately analyzed and given its broadest reasonable interpretation in light of and consistent with the written description”, and that “[t]he analysis of whether the specification complies with the written description requirement calls for the examiner to compare the scope of the claim with the scope of the description to determine whether applicant has demonstrated that the inventor was in possession of the claimed invention”.
The Definition of Terms and Pending Claim Scope Differs from Priority Documents
Regarding claims 1-8 and the disclosure of US Provisional Application 62/979,733 (filed 2/21/2020), it is noted that claims 1-8 are not disclosed or otherwise literally, inherently, or implicitly disclosed by Pro’733 commensurate in scope with the instant claims. More specifically, Pro’733 does not teach, disclose, or recite the word Nanobody®, does not disclose any fusion proteins comprising STINGΔTM having the sequence of instant SEQ ID NOs: 3-6 conjugated to sequences of instant SEQ ID NOs: 7-10, or otherwise disclose fusion proteins having the structures of instant SEQ ID NOs: 7-42. In addition, Pro’733 does not support limitations pertaining to percent identity such as “at least 75% . . . identity”. Accordingly, it is readily apparent that Pro’733 fails to include the subject matter, limitations, and terminology present in the instant disclosure, and therefore, consistent with MPEP § 2163.02, the Examiner concludes that the claimed subject matter is not described in Pro’733 in a manner permitting an artisan to conclude that Applicant described and had possession of the instant claim scope at the time Pro’733 was filed.
Regarding claims 1-8 and the disclosure of US Application 17/181,884 (filed 2/22/2021), it is noted that the pending claim scope of instant claims 1-8 is not disclosed or otherwise supported literally, inherently, or implicitly by App’884 using a disclosure commensurate in scope with the instant claims.
Regarding “percent identity” limitations at claims 2 and 7-8, it is readily apparent that these claims are not supported by App’884 because App’884 refers to “percent homology” rather than “percent identity”, and these are materially distinct concepts in the prior art (see, e.g., Rost4 at abs, 85 at col I-II at bridging ¶, which identifies that proteins can be 100% homologous while sharing less than 10% sequence identity).
Regarding instant claims 1-8 and the scope of “STINGΔTM protein”, although ostensibly and at first glance instant claims 1 and 3-6 appear to be supported by claims 1, 3, and 5-6 of App’884 (see, e.g., App’884 at claims 1, 3, and 5-6; compare id. with instant claims 1 and 3-6), this is incorrect because the meaning and scope of the terms differ between the instant application and App’884. This is pertinent because as noted above, a written description analysis requires an examiner to compare “the scope of the claim with the scope of the description”, and requires an Examiner to analyze whether or not a claim involves “subject matter” not present in an application, “involving a departure from, addition to, or deletion from the disclosure of the application as filed” (see, e.g., MPEP § 2163.02 and legal analysis provided above). In the instant case, the meaning and scope of the generic term “STINGΔTM” differs between the instant claims and App’884, because App’884 does not actually disclose instant sequences of SEQ ID NOs: 3-6 (compare instant SEQ ID NOs: 3-6 with App’884 at SEQ ID NOs: 3-6, showing less than 100% identity among prior and currently recited sequences). Accordingly, the scope and description of the term “STINGΔTM” materially differs between the instant application and App’884, because the sequences were altered upon filing the instant Application.
Regarding instant claims 1-8 and the scope of “nanobody”, although ostensibly and at first glance instant claims 1 and 3-6 appear to be supported by claims 1, 3, and 5-6 of App’884 (see, e.g., App’884 at claims 1, 3, and 5-6; compare id. with instant claims 1 and 3-6), this is incorrect because the meaning and scope of the terms differ between the instant application and App’884. This is pertinent as explained above, because a written description analysis requires an examiner to compare “the scope of the claim with the scope of the description”, and requires an Examiner to analyze whether or not a claim involves “subject matter” not present in an application, “involving a departure from, addition to, or deletion from the disclosure of the application as filed” (see, e.g., MPEP § 2163.02 and legal analysis provided above). Here, the meaning and scope of the term “nanobody” as used in App’884 materially differs in scope from the instant claims. As an initial matter, Nanobody® is a is a trade name or a mark used in commerce5, which is improperly and ambiguously utilized in the disclosure and claims of App’884 to refer to particular materials or products (see, e.g., MPEP § 2173.05(u)). In addition, App’884 provides zero examples of any products or structure/function relationships commensurate in scope with the functional limitations of instant claims 1 and 3-6 or claims 1, 3, and 5-6 of App’884 (see, e.g., App’884 at claims 1, 3, and 5-6; compare id. with instant claims 1 and 3-6). Finally, in the instant application, the term “nanobody” includes the scope of the specific sequences of instant SEQ ID NOs: 7-10, which were not disclosed by App’884 (compare instant SEQ ID NOs: 7-10 with App’884 at sequence listing, noting that instant SEQ ID NOs: 7-10 were newly added upon filing the instant Application).
Regarding instant claims 1-8 and the scope of “fusion proteins” comprising a “STINGΔTM protein” and a “nanobody”, although ostensibly and at first glance instant claims 1 and 3-6 appear to be supported by claims 1, 3, and 5-6 of App’884 (see, e.g., App’884 at claims 1, 3, and 5-6; compare id. with instant claims 1 and 3-6), this is incorrect because the meaning and scope of the terms differ between the instant application and App’884. This is pertinent as explained above, because a written description analysis requires an examiner to compare “the scope of the claim with the scope of the description”, and requires an Examiner to analyze whether or not a claim involves “subject matter” not present in an application, “involving a departure from, addition to, or deletion from the disclosure of the application as filed” (see, e.g., MPEP § 2163.02 and legal analysis provided above. Here, instant claims 1-8 include at least the embodiments of instant claim 8 (i.e., instant SEQ ID NOs: 11-42). However, instant SEQ ID NOs: 11-42 are not claimed, taught, or disclosed by App’884 (compare instant SEQ ID NOs: 11-42 with App’884 at sequence listing, noting that instant SEQ ID NOs: 11-42 were newly added upon filing the instant Application and do not correspond to any sequences of App’884).
In sum, in view of App’884 an artisan could not obtain the fusion proteins of instant SEQ ID NOs: 11-42 because (i) App’884 fails to disclose the protein sequences corresponding to the “STINGΔTM protein” of instant SEQ ID NOs: 3-6; (ii) App’884 fails to disclose the protein sequences corresponding to the “nanobodies” of instant SEQ ID NOs: 7-10; and (ii) App’884 fails to provide a definition or guidance that would reasonably direct an artisan to the claim scope and definitions currently set forth in the pending claims.
Conclusion
Guidance for determining whether or not a priority document provides written description support for pending claims is addressed at MPEP § 2163.02, which explains that
If a claim is amended to include subject matter, limitations, or terminology not present in the application as filed, involving a departure from, addition to, or deletion from the disclosure of the application as filed, the examiner should conclude that the claimed subject matter is not described in that application.
Here, the instant disclosure and claims markedly and materially differ from the disclosures of Pro’733 and App’884 in the manner in which terms are defined and utilized, including that the disclosures and claims of the priority documents did not include, describe, or disclose any of the subject matter corresponding to instant SEQ ID NOs: 3-42 as discussed above. Accordingly, relative to these priority documents, the instant disclosure is directed to subject matter and limitations not present or disclosed in Pro’733 and App’884, such that Applicant has added substantial and material subject matter going beyond the subject matter of Pro’733 and App’884 (see, e.g., MPEP § 2163(I)(B), explaining that the written description requirement “serves to prevent an applicant from adding information that goes beyond the subject matter originally filed”) in a manner that does not permit an artisan to recognize “that the inventor had possession at that time of the later claimed subject matter” (see, e.g., MPEP § 2163.02).
Accordingly, priority to US Provisional Application 62/979,733 (filed 2/21/2020) and Application No. 17/181,884 (filed 2/22/2021) are denied for claim 1 and all of the dependents of those claims (e.g., all presently examined claims); these claims have been accorded latter priority date of 5/04/2023 corresponding to the instant application of US Application 18/312,030 (filed 5/04/2023).
Claim Interpretation
For purposes of examination, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action. Applicant is advised that a specialized definition should be properly supported and specifically identified (see, e.g., MPEP § 2111.01(IV), describing how Applicant may act as their own lexicographer).
Claim 1 is representative of the pending claim scope and presently recites:
A fusion protein, comprising a STINGΔTM protein fused to a nanobody.
Applicable claim interpretations are discussed below.
“Comprising” is an open-ended transitional term (see, e.g., MPEP § 2111.03(I)), wherein additional steps or components are not excluded. However, “‘[c]omprising’ is a term of art used in claim language which means that the named elements are essential” (see, e.g., id.; see also Genentech, Inc. v. Chiron Corp., 112 F.3d 495, 501, 42 USPQ2d 1608, 1613 (Fed. Cir. 1997)).
“Consisting of” excludes any elements, step, or ingredient not specified (see, e.g., MPEP § 2111.03(II)). When the phrase "consists of" appears in a clause of the body of a claim, rather than immediately following the preamble, the "consisting of" phrase limits only the element set forth in that clause; other elements are not excluded from the claim as a whole (see, e.g., MPEP § 2111.03(II)).
A Nanobody®6 is understood to be “a single-domain antibody (sd Ab); an antibody fragment consisting of a single monomeric variable antibody domain” (see, e.g., Spec. filed 5/04/2023 at 8 at lines 8-10). The full scope of structures encompassed by Nanobody® is unlimited, but is understood to include at least any prior art sequence sharing at least 75% identity with any one of instant SEQ ID NOs: 7-10 in view of instant claim 7.
A “STINGΔTM” is understood to be the cytosolic domain of STING (“Stimulator of Interferon Genes”) (see, e.g., Spec. filed 5/04/2023 at 6 at lines 15-25). The structure of a “STINGΔTM” is understood to be satisfied by at least any sequence sharing at least 75% sequence identity with instant SEQ ID NOs: 3-6 in view of instant claim 2.
The “fusion protein” of claim 1 is understood to include at least any sequence sharing at least 75% identity to any of SEQ ID NOs: 11-42 in view of claim 8.
Examiner notes that “sequence identity”, “sequence similarity”, and “sequence homology” have been utilized in the instant disclosure and priority documents of record. Examiner notes that “sequence identity”, “sequence similarity”, and “sequence homology” are distinct concepts in the prior art. For example, Rost7 identifies that proteins can be 100% homologous while sharing less than 10% sequence identity (see, e.g., Rost at 85 at col I-II at bridging ¶; see also id. at abs). Rost specifically identifies that the terms “sequence identity”, “sequence similarity”, and “sequence homology” are not synonymous and have distinct, art-recognized definitions (see, e.g., Rost at 85 at col II at 1st full ¶, defining sequence identity; Rost at 86 at col II at § “Definition of sequence identity and sequence similarity”; Rost at 85 at abs, col I at § Introduction, identifying homology is not equivalent to identity).
Regarding claim 8: It is unclear if all polypeptides sharing at least 75% sequence identity with instant SEQ ID NOs: 7-10 satisfy all functional limitations recited at instant claims 4-6 or not. For purposes of examination under 35 USC 112, it is reasonably assumed that not all species within claim 8 satisfy the functional limitations of instant claims 4-6 (e.g., sequences sharing 75% identity, but having prolines or cystines at the remaining positions). This is consistent with the understanding in the prior art, that antigen-binding specificity can be altered or abrogated by a single amino acid substitution8.
Critically, “percent sequence identity” is defined in a manner differing from BLAST and other alignment programs (see, e.g., Spec. filed 5/04/2023 at 22 at lines 9-25), because “Gaps presented in the target sequence are not counted… gaps presented in the reference sequence are not counted” (see id). This is pertinent because although BLAST might report 362/370 identities in the following alignment:
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369
668
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In view of the special definition in the instant disclosure, this would be understood to be 362/363 identities, wherein the gap of 7 amino acids “are not counted” (see, e.g., Spec. filed 5/04/2023 at 22 at lines 9-25), which would yield 99.72% (362/363) identity rather than 97.83% (362/370) identity as shown by BLAST.
Additional claim interpretations have been set forth below.
Specification
The use of the term Nanobody® (Serial Number 85573029; Registration Number 5098047; Registration Date of 2016-12-13; Owner: ABLYNX (NAAMLOZE VENNOOTSCHAP (NV); BELGIUM); Technologiepark-Zwijnaarde 21, Gand, 9052, BELGIUM), which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 2 and 7-8 are objected to because of the following informalities:
Claims 2, 7, and 8 are objected to because each contains redundant and superfluous language that fails to meaningfully limit the pending claim scope. Specifically, these claims recite the phrase “at least 75%, 80%, 85%....or 100% identity to” one or more sequences, but only the recitation of “at least 75%” is limiting, because if something satisfies the broadest limitation, then it fully satisfies the entire claim scope; and if something satisfies the most stringent limitation (e.g., 100%”) then it must necessarily and inherently also satisfies the broader limitation (e.g., if something is 100% identical, it is also at least 75% identical). Accordingly, such limitations within the same claim are non-limiting and superfluous. Redundant and superfluous language should be removed to enhance claim clarity and to minimize potential confusion.
Appropriate correction is required.
Claim Rejections
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-8 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.
Claims 1 and 3-7 contains the trademark/trade name Nanobody® (Serial Number 85573029; Registration Number 5098047; Registration Date of 2016-12-13; Owner: ABLYNX (NAAMLOZE VENNOOTSCHAP (NV); BELGIUM); Technologiepark-Zwijnaarde 21, Gand, 9052, BELGIUM). Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a particular polypeptide sequence and, accordingly, the identification/description is indefinite.
Claims 4-6 attempt to define a subgenus of “nanobodies” having unknown structural metes and bounds by reciting a function that the desired “nanobodies” are supposed to achieve, but these functions do not correspond to any structure/function relationship of record, commensurate in scope with the claims. Per MPEP § 2173.05(g),
[T]he use of functional language in a claim may fail "to provide a clear-cut indication of the scope of the subject matter embraced by the claim" and thus be indefinite. In re Swinehart, 439 F.2d 210, 213 (CCPA 1971). For example, when claims merely recite a description of a problem to be solved or a function or result achieved by the invention, the boundaries of the claim scope may be unclear. . .
Here, the claims merely recite a description of functions or results to be achieved by the invention rather than a description of the structures capable of achieving the desired functions, and therefore the claims are indefinite per MPEP § 2173.05(g). MPEP § 2173 identifies that the primary purpose of the requirement is to inform the public of the boundaries of what constitutes infringement of the patent, but here it is unclear what compounds do or do not infringe upon the scope of claims 4-6 because it is prima facie unclear what does or does not constitute the metes and bounds of “nanobodies”. Although it is reasonably assumed that the limitations of claims 4-6 may be fully satisfied by SEQ ID NOs: 7-10, zero additional guidance or structure/function teachings are presented identifying any functional sequences sharing less than 100% sequence identity with instant SEQ ID NOs: 7-10. Notably, the courts have stated that
Regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to the subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.” University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1984 (CAFC 2004) (emphasis added).
Accordingly, because it is unclear what compounds do or do not satisfy the functional limitations of claims 4-6, and an artisan would be unable to identify infringing from non-infringing compounds, claims 4-6 are rejected as indefinite.
Claim 8 recites and refers to “residues in parentheses”. There is insufficient antecedent basis for this limitation in the claim.
Claims 2-8 depend directly or indirectly from an indefinite base claim and fail to rectify the indefiniteness of the base claim. Accordingly, these claims are rejected as depending upon an indefinite base claim.
Accordingly, claims 1-8 are rejected as indefinite.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 7 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 7 depends from claim 6, wherein claim 6 is limited to a Nanobody® compound “capable of binding to CTLA4 or PD-L1”. Claim 7 is understood to be substantially broader than claim 6, at least because claim 7 explicitly includes any sequences sharing at least 75% sequence identity to the EIIIB binder of SEQ ID NO: 10 (see, e.g., Spec. filed 5/04/2023 at 9 at lines 1-20, noting that SEQ ID NO: 10 is not identified as a PD-L1 or CTLA4 binding peptide as required by claim 6 from which claim 7 depends). Accordingly, claim 7 is rejected as failing to include all the limitations of the claim upon which it depends because it is reasonably understood to more broadly includes sequences not capable of binding to CTLA4 or PD-L1 as required by claim 6.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 7 is rejected.
Claim Rejections - 35 USC § 112(a), Written Description
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 4-7 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.
Brief Statement of the Issue(s)
Claims 4-7 are understood to recite functional limitations that do not correspond to a structure/function relationship of record reasonably permitting an artisan to identify included or excluded Nanobody® sequences.
Claim Scope
Claims 4-7 are representative of the pending claims scope and each of claims 4-6 recite a functional limitation (e.g., “the nanobody is capable of binding to a cancer cell or tumor extracellular matrices” at claim 4; “the nanobody is capable of binding to CTLA4 or PD-L1” at claim 6, etc.).
The applicable claim interpretations have been set forth above under 35 USC 112(b) and in a separate claim interpretation section. Those discussions are incorporated herein.
It is unclear if the claim scope encompass trillions of species or perhaps only a few in view of the functional limitations set forth in the claim(s). Accordingly, the claim scope reasonably appears to be vast and highly varied.
Actual Reduction to Practice
It is understood that only examples of Nanobody® sequences capable of binding to PDL1, CTLA4, and EIIIB have been disclosed and exemplified on record (see, e.g., Spec. filed 5/04/2023 at page 8 at line 28 to page 9 at line 20). All disclosed fusion proteins (e.g., instant SEQ ID NOs:11-42) comprise one of these four sequences (see, e.g., Spec. filed 5/04/2023 at page 8 at line 28 to page 9 at line 20, disclosing instant SEQ ID NO: 7-10, wherein SEQ ID NOs: 7-8 bind PDL1, SEQ ID NO: 9 binds CTLA4, and SEQ ID NO: 10 binds to EIIIB).
Zero species of nanobodies capable of binding to PD-L2, A2AR, B7-H3, B7-H4, BTLA, KIR, LAG3, TIM-3, TIGIT, NGK2A, PSGL-1 or VISTA were taught, disclosed, or otherwise reduced to practice.
Only one species of sdAb was disclosed capable of binding to EIIIB, namely instant SEQ ID NO: 10.
Only one species of sdAb was disclosed capable of binding to CTLA4, namely instant SEQ ID NO: 9.
Only two species of sdAb were disclosed capable of binding to PDL1, namely instant SEQ ID NOs: 7-8.
Zero species of sdAb lacking 100% identity with instant SEQ ID NO: 7, 8, 9, or 10 were reduced to practice.
Assessment of whether disclosed species are representative of the claimed genus
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus (see, e.g., MPEP § 2163(II)(3)(a), MPEP §2163.03(V)). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
In this case, the claims encompass an essentially infinite number of products including highly diverse Nanobody® sequences, but only reduce to practice and specifically teach a very limited number of sdAb sequences.
Although the MPEP does not define what constitutes a sufficient number of representative species, the Courts have indicated that the disclosure of two species within a subgenus did not describe that subgenus. In re Gostelli, 872 F.2d at 1012, 10 USPQ2d at 1618. Similarly, the disclosure of zero nanobodies capable of targeting PD-L2, A2AR, B7-H3, B7-H4, BTLA, KIR, LAG3, TIM-3, TIGIT, NGK2A, PSGL-1 or VISTA of the claimed invention does not provide sufficient disclosure to satisfy the written description requirement for the instantly claimed genus. In addition, the disclosure of only one Nanobody® capable of binding to CTLA4 does not provide sufficient disclosure to satisfy the written description requirement for the instantly claimed genus. In addition, the disclosure of only one Nanobody® capable of binding to EIIIB does not provide sufficient disclosure to satisfy the written description requirement for the instantly claimed genus. Finally, the disclosure of only two nanobodies capable of binding to PDL1 does not provide sufficient disclosure to satisfy the written description requirement for the instantly claimed genus of millions of sequences.
Identifying characteristics of the genus
In the absence of a reduction to practice of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
Upon review, the originally filed disclosures provides no structural guidance regarding what structures do or do not satisfy the functional limitations of instant claims 4-7 because the originally filed disclosure fails to set forth any structure/function relationships commensurate in scope with the functional limitations of instant claims 4-6.
It is acknowledged that claim 7 ostensibly appears to provide structural guidance regarding sequences capable of “binding to CTLA4 or PD-L1”, namely any sequence sharing “at least 75% . . . identity to” one of SEQ ID NOs: 7-10 (see, e.g., instant claim 7). However, such a claim is not credible or supported by objective evidence. Notably, SEQ ID NO: 10 is not even disclosed as capable of binding CTLA4 or PDL1, which casts doubt on the pending claims scope (see, e.g., Spec. filed 5/04/2023 at 9 at lines 1-20, noting that SEQ ID NO: 10 is not identified as a PD-L1 or CTLA4 binding peptide as required by claim 6 from which claim 7 depends). In addition, it is noted that the scope of just sequences sharing 75% identity with instant SEQ ID NO: 7 (i.e., a 122-mer) would include 2030-1 sequences (>>trillions)9, including sequences containing 30 proline or 30 cystine residues. It is not credible that all such sequences would be capable of “specifically” binding to PDL1. In fact, the prior art teaches and suggests that even a single amino acid substitution may be sufficient to abrogate the specificity of an antibody-based compound10, and the instant disclosure provides zero supporting disclosure addressing the concerns and basic understanding of antibody specificity in the prior art.
Accordingly, no specific guidance to any other Nanobody® or sdAb capable of satisfying the functional limitations of instant claims 4-7, other than instant SEQ ID NOs: 7-10 are provided in the originally filed disclosure.
Accordingly, the functional limitation of claims 4-6 are only utilized as a vague attempt to capture unknown and undisclosed structures, sufficient to achieve some functional result that Applicant hopes and desires that the disclosed invention is able to achieve. However, the disclosure but does not meaningfully disclose an unambiguous structure/function relationship permitting an artisan to identify, a priori, which exact structures do or do not satisfy the functional limitations at issue.
Predictability in the Art
Although the level of skill in the art is high, the predictability in the art is low due to the complexity of biological systems, biochemistry, and the ability to determine sdAb (Nanobody®) specificity de novo. Specifically, an artisan would not be able to predict or identify, a priori, and in the absence of any guidance or consensus structures exactly what compounds would (or would not) be capable of satisfying the functional limitations of claims 4-7.
Accordingly, in the absence of sufficient structure/function teachings identifying particular compounds capable of satisfying the functional limitations of instant claims 4-7, as required to practice the full scope of the claims, an artisan would not reasonably conclude that Applicant possessed the full scope of the broad and highly varied claim scope.
Conclusion
The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does "little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). The courts have stated that “merely drawing a fence around a perceived genus is not a description of the genus. One needs to show that one has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus” (see, e.g., AbbVie v. Janssen, 111 USPQ2d 1780 (Fed. Cir. 2014) at 1789). In addition, the Courts have stated
“[r]egardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to the subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.” University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1984 (CAFC 2004) (emphasis added).
This is pertinent because, in the instant case, Applicants have claimed a broad and highly varied genus comprising an unknown number of species defined by reference to one or more functional limitations; however, the originally filed disclosure has failed to identify any common structure/function relationship sufficient to permit an artisan to identify what structures are included or excluded by the claim scope. This also means that it is prima facie unclear what structures infringe or do not infringe upon the pending claim scope.
In conclusion, for the reasons discussed above, the skilled artisan would not reasonably conclude that the inventor(s), at the time the application was filed, had possession of the full scope of the claimed invention.
Accordingly, claims 4-7 are rejected.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-8 are rejected under 35 U.S.C. 103 as being unpatentable over US2020/0199169A1 (Jun. 25, 2020), and further in view of PDB: 5DXW_A11.
Claim interpretation: The applicable claim interpretation has been set forth in a preceding section above, and those interpretations are incorporated into the instant rejection. Additional claim interpretations are set forth below.
Regarding instant claims 1-8, US’169 teaches and identifies that art-recognized Immune Checkpoint Inhibitors include a PD-1 pathway antagonist (see, e.g., US’169 at ¶¶[0057], [0058], [0079], [0092], [0101], [0107]), wherein PD-1 pathway antagonist explicitly includes an anti-PD-l1 antibody (see, e.g., US’169 at ¶[0101]), wherein an “antibody” is disclosed as including fragments of antibodies capable of specifically binding an antigen or epitope (see, e.g., US’169 at ¶[0058]). US’169 explicitly exemplifies anti-PD-L1 antibody molecules that may comprise SEQ ID NO: 9 (see, e.g., US’169 at ¶[00108]), wherein SEQ ID NO: 9 is subsequently identified as human STING AA140-379 (see, e.g., US’169 at ¶¶[0334]-[0337], SEQ ID NO: 9), which has the sequence of:
APAEISAVCEKGNFNVAHGLAWSYYIGYLRLILPELQARIRTYNQHYNNLLRGAVSQRLYILLPLDCGVPDNLSMADPNIRFLDKLPQQTGDRAGIKDRVYSNSIYELLENGQRAGTCVLEYATPLQTLFAMSQYSQAGFSREDRLEQAKLFCRTLEDILADAPESQNNCRLIAYQEPADDSSFSLSQEVLRHLRQEEKEEVTVGSLKTSAVPSTSTMSQEPELLISGMEKPLPLRTDFS
(compare US’169 at SEQ ID NO: 9 with instant SEQ ID NO: 7, showing 100% identity over positions 2-241 of instant SEQ ID NO: 7; or 240/241 (99.58%) identities over the length of SEQ ID NO: 7).
US’169 differs from the instant claim scope as follows: Although the PD-L1 antibody of US’169, comprises human STING AA140-379, it does not comprise the sdAb sequence of instant SEQ ID NO: 7.
Instant SEQ ID NO: 7 was taught and disclosed as positions 3-124 of 5DXW (compare instant SEQ ID NO: 7 with 5DXW at positions 3-124, showing 100% sequence identity over the full-length of instant SEQ ID NO: 7, and 122/130 residues of 5DXW12). Critically, 5DXW was taught and recognized in the prior art as a “PD-1L Nanobody” circa 2016 (see 5DXW at 1 at Title), and is therefore a prior art element.
Accordingly, the issue is whether or not it would have been obvious to simply combine or substitute the prior art sequence of 5DXW with STING AA140-379 in the PD-L1 antibodies and antagonist structures taught and disclosed by the primary reference. Critically, the primary reference teaches and discloses that PD-1 pathway antagonists include any anti-PD-L1 antibody (see, e.g., US’169 at ¶[0101]), wherein an “antibody” is disclosed as including fragments of antibodies capable of specifically binding an antigen or epitope (see, e.g., US’169 at ¶[0058]). Accordingly, an artisan would readily appreciate that STING AA140-379 could be combined with 5DXW to predictably yield a PD-1 pathway antagonist, namely an anti-PD-L1 antibody that would be predicted and expected to act as a PD-1 pathway antagonist and to specifically bind PD-L1. Such a construct would be understood to comprise either STING AA140-379 or 5DXW at the N-termini or the C-termini, yielding either
APAEISAVCEKGNFNVAHGLAWSYYIGYLRLILPELQARIRTYNQHYNNLLRGAVSQRLYILLPLDCGVPDNLSMADPNIRFLDKLPQQTGDRAGIKDRVYSNSIYELLENGQRAGTCVLEYATPLQTLFAMSQYSQAGFSREDRLEQAKLFCRTLEDILADAPESQNNCRLIAYQEPADDSSFSLSQEVLRHLRQEEKEEVTVGSLKTSAVPSTSTMSQEPELLISGMEKPLPLRTDFSMAQVQLVETGGGLVQPGGSLRLSCTASGFTFSMHAMTWYRQAPGKQRELVAVITSHGDRANYTDSVRGRFTISRDNTKNMVYLQMNSLKPEDTAVYYCNVPRYDSWGQGTQVTVSSGGLPETGGHHHHHH
or
MAQVQLVETGGGLVQPGGSLRLSCTASGFTFSMHAMTWYRQAPGKQRELVAVITSHGDRANYTDSVRGRFTISRDNTKNMVYLQMNSLKPEDTAVYYCNVPRYDSWGQGTQVTVSSGGLPETGGHHHHHHAPAEISAVCEKGNFNVAHGLAWSYYIGYLRLILPELQARIRTYNQHYNNLLRGAVSQRLYILLPLDCGVPDNLSMADPNIRFLDKLPQQTGDRAGIKDRVYSNSIYELLENGQRAGTCVLEYATPLQTLFAMSQYSQAGFSREDRLEQAKLFCRTLEDILADAPESQNNCRLIAYQEPADDSSFSLSQEVLRHLRQEEKEEVTVGSLKTSAVPSTSTMSQEPELLISGMEKPLPLRTDFS
Both possibilities satisfy claims 1-7 and comprise sequences sharing 100% sequence identity with instant SEQ ID NO: 4 and SEQ ID NO: 7. Regarding instant claim 8, the second possible sequence shown above shares 362/368 residues (98.36% identity) with instant SEQ ID NO: 27, wherein positions 1-31 are optionally absent (compare instant SEQ ID NO 27 with US’169 at SEQ ID NO: 9 and 5DXW).
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s): The claimed invention is the combination (or simple substitution) or prior art elements (i.e., the known STING AA140-379 of the primary reference, and the known 5DXW sdAB sequence) according to known methods of forming PD-1 pathway antagonists, namely an anti-PD-L1 antibody, as taught and disclosed by the primary reference, wherein the claimed invention is the simple substitution of one known equivalent PD-1L antibody or antibody fragment for another (see, e.g., MPEP §§ 2143(I)(A), (B), 2144.06(I)-(II)). Furthermore, each portion was individually known in the prior art and merely perform there art-recognized function in combination as they do separately.
No evidence of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record to date.
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well within the ordinary skill in the art to make and use an anti-PD-L1 antibody with domains taught and disclosed in the prior art combined together to predictably yield a compound that would act as a PD-L1 antibody exactly as taught and suggested by the prior art.
Accordingly, claims 1-8 are rejected.
Claims 1-8 are rejected under 35 U.S.C. 103 as being unpatentable over US2021/0277077 (Sep. 9, 2021) in view of PDB: 5DXW_A13.
Claim interpretation: The applicable priority date for instant claims 1-8, as relevant to the originally elected species, is understood to be 5/04/2023 corresponding to the filing date of US Application 18/312,030. The applicable claim interpretation has been set forth in a preceding section above, and those interpretations are incorporated into the instant rejection. Additional claim interpretations are set forth below.
Regarding instant claims 1-8, US’077 teaches and discloses fusion proteins comprising STINGΔTM conjugated to a “nanobody” sdAb, wherein the STINGΔTM may comprise or consist of SEQ ID NOs: 3-6, and wherein the nanobody is capable of binding to PD-L1 of CTLA4, and is fused to the N-terminus of the STINGΔTM (see, e.g., US’077 at claims 1-2, 5-6, 11-13, SEQ ID NOs: 1-6; compare US’077 at SEQ ID NO: 3 with instant SEQ ID NO: 4, noting 240/241 identities, or 99.56% sequence identity). Accordingly, the prior art directs artisans to fusion constructs comprising sdAb capable of targeting PD-L1 conjugated to the N-terminal of STINGΔTM.
US’077 differs from the instant claim scope as follows: US’077 does not actually teach, disclose, or exemplify any “nanobodies” capable of binding to PD-L1. Therefore, the relevant issue is whether or not it would have been obvious to review the prior art for known “nanobodies”, and then to simply create a species of US’077 by combining a prior art sdAb (Nanobody®) to the N-terminal of STINGΔTM in view of the prior art.
A sdAb (“nanobody”) capable of targeting PD-L1 was already known in the prior art as established by 5DXW, which discloses that instant SEQ ID NO: 7 was taught and disclosed as positions 3-124 of 5DXW (compare instant SEQ ID NO: 7 with 5DXW at positions 3-124, showing 100% sequence identity over the full-length of instant SEQ ID NO: 7, and 122/130 residues of 5DXW14). Critically, 5DXW was taught and recognized in the prior art as a “PD-1L Nanobody” circa 2016 (see 5DXW at 1 at Title).
An artisan following the guidance of US’077 using the sequence of 5DXW would arrive at a combined sequence such as 5DXW conjugated to the N-terminus of SEQ ID NO: 3 of US’077, which would yield a fusion protein comprising or consisting of:
MAQVQLVETGGGLVQPGGSLRLSCTASGFTFSMHAMTWYRQAPGKQRELVAVITSHGDRANYTDSVRGRFTISRDNTKNMVYLQMNSLKPEDTAVYYCNVPRYDSWGQGTQVTVSSGGLPETGGHHHHHHLAPAEISAVCEKGNFNVAHGLAWSYYIGYLRLILPELQARIRTYNQHYNNLLRGAVSQRLYILLPLDCGVPDNLSMADPNIRFLDKLPQQTGDHAGIKDRVYSNSIYELLENGQRAGTCVLEYATPLQTLFAMSQYSQAGFSREDRLEQAKLFCRTLEDILADAPESQNNCRLIAYQEPADDSSFSLSQEVLRHLRQEEKEEVTVGSLKTSAVPSTSTMSQEPELLISGMEKPLPLRTDFS
This structure aligns with instant SEQ ID NO: 27 sans optional residues 1-3115 as follows:
PNG
media_image2.png
314
656
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Greyscale
Accordingly, there is a 6-mer gap and 1 mismatch in the alignment, which would typically be considered 362/369 residues (98.10% identity), but the instant application and pending claims define “percent sequence identity” in a manner that does not count gaps (see, e.g., Spec. filed 5/04/2023 at 22 at lines 9-25, explaining that for purposes of the claims “Gaps presented in the target sequence are not counted… gaps presented in the reference sequence are not counted” (see id). Accordingly, ignoring the single gap per the instant definitions means that the sequences share 362/363 residues or 99.72% identity and differ by a single His/Arg mutation (compare alignment with instant claims 2 and 7-8, noting that irrespective of the “gap” interpretation, the explicitly recited limitations are fully satisfied).
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s): The claimed invention is the combination of prior art elements (i.e., a known STINGΔTM taught by the primary reference, a known “nanobody” of 5DXW) according to known methods of forming a fusion protein comprising a “nanobody” fused to the N-termini of a STINGΔTM sequence exactly as taught and disclosed by the primary reference, wherein each prior art element would merely perform its art-recognized function in combination as it does separately (see, e.g., MPEP §§ 2143(I)(A)).
No evidence of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record to date.
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well within the ordinary skill in the art to make a fusion protein as taught by the primary reference by reviewing the prior art and identifying known sequences, wherein the fusion protein merely performs as expected and taught by the primary reference.
Accordingly, claims 1-8 are rejected.
Claims 1-8 are rejected under 35 U.S.C. 103 as being unpatentable over US2021/0277077 (Sep. 9, 2021) in view of PDB: 5DXW_A16 as applied to claims 1-8 above, and further in view of Terpe17, Livingstone et al18 and US2020/0199169A1 (Jun. 25, 2020).
Claim interpretation: This rejection addresses the originally elected species. The applicable priority date for instant claims 1-8, as relevant to the originally elected species, is understood to be 5/04/2023 corresponding to the filing date of US Application 18/312,030. The applicable claim interpretation has been set forth in a preceding section above, and those interpretations are incorporated into the instant rejection. Additional claim interpretations are set forth below.
The teachings of US2021/0277077 (Sep. 9, 2021) in view of 5DXW as applied to claims 1-8 have been set forth above in a previous rejection, and those teachings are incorporated into the instant rejection. The instant rejection addresses the originally elected species of instant SEQ ID NO: 27 lacking optional residues 1-3119. The alignment shown above is between the prior art embodiment of SEQ ID NO: 3 of US’077 conjugated at the N-termini to the sequence of 5DXW, and as shown in the preceding rejection (incorporated herein), this embodiment of the prior art differs from the originally elected species at two points: (i) a gap corresponding to “HHHHHH” at the end of the 5DXW sequence, and (ii) a histidine to arginine mutation at position circa position 224 (see alignment above).
US’077 in view of 5DXW differ from the originally elected species as follows: The “nanobody” of 5DXW contains a “HHHHHH” motif, and SEQ ID NO: 3 of US’077 contains a histidine rather than an arginine circa position 224. Therefore, the relevant issue is whether or not such changes render the originally elected species non-obvious in view of the prior art.
Regarding the polyhistidine motif of 5DXW, an artisan would readily appreciate that the “HHHHHH” motif of 5DXW corresponded to a well-known and art-recognized polyhistidine tag (see, e.g., Terpe at title, abs, Tables 1-2 on 524). Terpe identifies that histidine tags are affinity tags, which are used to facilitate purification of recombinant polypeptides (see, e.g., Terpe at 523 at col I-II at § Introduction). Specifically, Terpe identifies that polyhistidine-tags or “HIS-tag[s]” are “a widely employed method” used to purify recombinant proteins (see, e.g., Terpe at 524-525 at § “Polyhistidine-tag (His-tag)”), that a poly-His affinity tag usually comprises 2-10 histidine residues (see, e.g., Terpe at Table 2 on 524), and that “[p]oly-histidine affinity tags are commonly placed on either the N- or the C-terminus of recombinant proteins” (see, e.g., Terpe at 525 at col II at 1st full ¶). Accordingly, an artisan would readily appreciate that because polyhistidine tags are commonly placed at the N- or the C-termini, that the polyhistidine tag of 5DXW should not be included when the sequence is fused to the N-termini of a STINGΔTM sequence as taught and suggested by US’077, because direct substitution would place the tag at an internal position rather than at a terminus. Accordingly, an artisan combining the “nanobody” of 5DXW to a STINGΔTM sequence as taught and suggested by US’077 would reasonably appreciate what the “HHHHHH” motif did and would readily appreciate that it could and should be removed in a fusion construct. Accordingly, in view of US’077, 5DXW, and Terpe an artisan would arrive at a fusion protein comprising or consisting of:
MAQVQLVETGGGLVQPGGSLRLSCTASGFTFSMHAMTWYRQAPGKQRELVAVITSHGDRANYTDSVRGRFTISRDNTKNMVYLQMNSLKPEDTAVYYCNVPRYDSWGQGTQVTVSSGGLPETGGLAPAEISAVCEKGNFNVAHGLAWSYYIGYLRLILPELQARIRTYNQHYNNLLRGAVSQRLYILLPLDCGVPDNLSMADPNIRFLDKLPQQTGDHAGIKDRVYSNSIYELLENGQRAGTCVLEYATPLQTLFAMSQYSQAGFSREDRLEQAKLFCRTLEDILADAPESQNNCRLIAYQEPADDSSFSLSQEVLRHLRQEEKEEVTVGSLKTSAVPSTSTMSQEPELLISGMEKPLPLRTDFS
Which differs from the originally elected species at a single position, highlighted above.
Regarding the single histidine/arginine mutation, the remaining difference is the sole mutation of histidine rather than arginine as shown above. However, such difference does not render the pending claim scope non-obvious as follows:
First, histidine and Arginine are conservative substitutions known in the prior art (see, e.g., Livingstone at Fig. 1 on 747). This is pertinent because MPEP § 2144.08(II)(A)(4)(c) states that some differences may be “of little importance”, and identifies that “In the area of biotechnology, an exemplified species may differ from a claimed species by a conservative substitution ("the replacement in a protein of one amino acid by another, chemically similar, amino acid... [which] is generally expected to lead to either no change or only a small change in the properties of the protein." Dictionary of Biochemistry and Molecular Biology 97 (John Wiley & Sons, 2d ed. 1989))”). Accordingly, the conservative substitution of one positively charged amino acid for another would be predicted to “lead to either no change or only a small change” absent objective evidence to the contrary, and no such evidence has been placed on record at this time.
Second, US’169 explicitly teaches and discloses STING peptides at SEQ ID NOs: 9-11 (see, e.g., US’169 at ¶¶[0334]-[0341], SEQ ID NOs: 9-11), which explicitly exemplify that STING sequences may have either an Arginine or Histidine at the position at issue (compare US’169 at ¶[0337] and SEQ ID NO:9 with US’169 at ¶[0340]-[0341] and SEQ ID NOs: 10-11, showing that the Wildtype SEQ ID NO: 9 STING sequence comprises arginine, but that a “reference” sequence SEQ ID NO: 10 has a histidine). US’169 further elaborates that “Human STING has known polymorphisms, including alleles encoding histidine at position 232” (see, e.g., US’169 at ¶[0051], noting that this is understood to be the instant position at issue upon alignment and recognition that leader sequences deemed “optional” differ or are otherwise absent, which alter position numbers).
In sum, STING sequences having a histidine or arginine at the position at issue were already known and taught in the prior art (see, e.g., US’169 at ¶¶[0334]-[0341], SEQ ID NOs: 9-11), and an artisan would readily appreciate that such a mutation is a conservative substitution not expected to substantially alter activity in view of Livingstone and MPEP § 2144.08(II)(A)(4)(c). Accordingly, an artisan would readily appreciate that the combined teachings of the prior art would reasonably direct an artisan to a fusion protein having a sequence such as
MAQVQLVETGGGLVQPGGSLRLSCTASGFTFSMHAMTWYRQAPGKQRELVAVITSHGDRANYTDSVRGRFTISRDNTKNMVYLQMNSLKPEDTAVYYCNVPRYDSWGQGTQVTVSSGGLPETGGLAPAEISAVCEKGNFNVAHGLAWSYYIGYLRLILPELQARIRTYNQHYNNLLRGAVSQRLYILLPLDCGVPDNLSMADPNIRFLDKLPQQTGD[HR]AGIKDRVYSNSIYELLENGQRAGTCVLEYATPLQTLFAMSQYSQAGFSREDRLEQAKLFCRTLEDILADAPESQNNCRLIAYQEPADDSSFSLSQEVLRHLRQEEKEEVTVGSLKTSAVPSTSTMSQEPELLISGMEKPLPLRTDFS
Where the brackets show known and acceptable substitutions for STING, known in the prior art. Critically, this narrow genus shares 100% sequence identity with the originally elected species of instant SEQ ID NO: 27.
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s): The claimed invention is the substitution and/or combination of prior art elements (i.e., a known STING sequences taught by the primary reference and by US’169, a known “nanobody” of 5DXW having a known polyhistidine tag as taught by Terpe) according to known methods of forming a fusion protein comprising a “nanobody” fused to the N-termini of a STINGΔTM sequence as taught and disclosed by the primary reference, wherein each prior art element would merely perform its art-recognized function in combination as it does separately (see, e.g., MPEP §§ 2143(I)(A)). Furthermore, per MPEP § 2144.09(I), a prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities, and here the chemical compounds share almost 100% sequence identity, have the exact same disclosed utility, and only differ by art-recognized, acceptable substitutions for STING (i.e., arginine with histidine) and by placement and usage of an art-recognized polyhistidine tag; accordingly such differences do not render the originally elected species non-obvious in view of the prior art because no evidence of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record to date, and because
"[W]hen 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." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 , 417 , 127 S. Ct. 1727 , 167 L. Ed. 2d 705 (2007) (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273 , 282 , 96 S. Ct. 1532 , 47 L. Ed. 2d 784 (1976)).
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well within the ordinary skill in the art to make a fusion protein as taught by the primary reference by reviewing the prior art and identifying known sequences and known variations.
Accordingly, claims 1-8 are rejected.
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
He et al.20, pertains to STINGΔTM as a construct used to facilitate delivery of small molecules (see, e.g., He2020 at title, abs, passim). He2020 teaches and discloses the usage of STINGΔTM as a delivery platform capable of triggering STING signaling independent of endogenous STING functionality, which desirably is capable of addressing cells that are STING deficient or defective due to genetic heterogeneity or cancer (see, e.g., He2020 at 1 at col II at final ¶ to 2 at col I at 1st partial ¶, Fig. 1 on 2, Fig. 3 on 3). The sequence for STINGΔTM is identified as positions 139-379 of human STING (see, e.g., He2020 at 9 at col II at § “Materials and Methods”). In sum, utilizing STINGΔTM as a delivery platform was known in the prior art. In addition, He2020 explicitly teaches, discloses, and suggests making and utilizing a genetic fusion of STINGΔTM “with tumor-specific antigen peptides”, which is predicted and expected to “enable simultaneous delivery of STING agonist-based adjuvant and antigens into dendritic cells to maximize the immune response” (see, e.g., He2020 at 9 at col II at § “Discussion”).
US20230210968 (corresponding to US Application 18/001,161) pertains to STINGΔTM sequences conjugated to tumor epitopes (see App’161 at claims filed 12/09/2025 at claim 1). However, the “tumor epitopes” do not appear to be identical to instant “nanobodies” in view of the instant record.
Conclusion
No claims are allowed.
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/RANDALL L BEANE/ Primary Examiner, Art Unit 1654
1 PDL1 is Anti-programmed death ligand 1.
2 SEQ ID NO: 7 is identified as a PD-L1 binder in the Specification and has the sequence of QVQLVETGGGLVQPGGSLRLSCTASGFTFSMHAMTWYRQAPGKQRELVAVITSHGDRANYTDSVRGRFTISRDNTKNMVYLQMNSLKPEDTAVYYCNVPRYDSWGQGTQVTVSSGGLPETGG.
3 SEQ ID NO: 4 is identified as human STINGΔTM in the specification and has the sequence of LAPAEISAVCEKGNFNVAHGLAWSYYIGYLRLILPELQARIRTYNQHYNNLLRGAVSQRLYILLPLDCGVPDNLSMADPNIRFLDKLPQQTGDRAGIKDRVYSNSIYELLENGQRAGTCVLEYATPLQTLFAMSQYSQAGFSREDRLEQAKLFCRTLEDILADAPESQNNCRLIAYQEPADDSSFSLSQEVLRHLRQEEKEEVTVGSLKTSAVPSTSTMSQEPELLISGMEKPLPLRTDFS.
4 Rost, Twilight zone of protein sequence alignments, Protein Engineering, vol. 12(2):85-94 (1999).
5 Nanobody®, Serial Number 85573029; Registration Number 5098047; Registration Date of 2016-12-13; Owner: ABLYNX (NAAMLOZE VENNOOTSCHAP (NV); BELGIUM); Technologiepark-Zwijnaarde 21, Gand, 9052, BELGIUM.
6 Nanobody®, Serial Number 85573029; Registration Number 5098047; Registration Date of 2016-12-13; Owner: ABLYNX (NAAMLOZE VENNOOTSCHAP (NV); BELGIUM); Technologiepark-Zwijnaarde 21, Gand, 9052, BELGIUM.
7 Rost, Twilight zone of protein sequence alignments, Protein Engineering, vol. 12(2):85-94 (1999).
8 Rudikoff et al., Single amino acid substitution altering antigen-binding specificity. Proc Natl Acad Sci U S A. 1982 Mar;79(6):1979-83. doi: 10.1073/pnas.79.6.1979. PMID: 6804947; PMCID: PMC346105; hereafter “Rudikoff”; at title, abs, passim.
9 122*0.25 is 30. Therefore, sequences sharing 75% identity of a 122-mer may differ at 30 residues, which may be selected from at least 20 proteinogenic amino acids.
10 Rudikoff et al., Single amino acid substitution altering antigen-binding specificity. Proc Natl Acad Sci U S A. 1982 Mar;79(6):1979-83. doi: 10.1073/pnas.79.6.1979. PMID: 6804947; PMCID: PMC346105; hereafter “Rudikoff”; at title, abs, passim.
11 PDB: 5DXW_A, Chain A, Pd-l1 nanobody, 130 aa, 23-MAY-2016, attached as 2 pages, also available at https://www.ncbi.nlm.nih.gov/protein/1031954647?sat=47&satkey=18041010 (last visited March 2, 2026); hereafter “5DXW”.
12 >pdb|5DXW|A Chain A, Pd-l1 Nanobody
MAQVQLVETGGGLVQPGGSLRLSCTASGFTFSMHAMTWYRQAPGKQRELVAVITSHGDRANYTDSVRGRFTISRDNTKNMVYLQMNSLKPEDTAVYYCNVPRYDSWGQGTQVTVSSGGLPETGGHHHHHH
13 PDB: 5DXW_A, Chain A, Pd-l1 nanobody, 130 aa, 23-MAY-2016, attached as 2 pages, also available at https://www.ncbi.nlm.nih.gov/protein/1031954647?sat=47&satkey=18041010 (last visited March 2, 2026); hereafter “5DXW”.
14 >pdb|5DXW|A Chain A, Pd-l1 Nanobody
MAQVQLVETGGGLVQPGGSLRLSCTASGFTFSMHAMTWYRQAPGKQRELVAVITSHGDRANYTDSVRGRFTISRDNTKNMVYLQMNSLKPEDTAVYYCNVPRYDSWGQGTQVTVSSGGLPETGGHHHHHH
15 See, e.g., Spec. filed 5/04/2023 at SEQ ID NO: 27 at page 12, sequence listing noting that positions 1-31 are optionally absent.
16 PDB: 5DXW_A, Chain A, Pd-l1 nanobody, 130 aa, 23-MAY-2016, attached as 2 pages, also available at https://www.ncbi.nlm.nih.gov/protein/1031954647?sat=47&satkey=18041010 (last visited March 2, 2026); hereafter “5DXW”.
17 Terpe, Overview of tag protein fusions: from molecular and biochemical fundamentals to commercial systems, Appl. Microbiol. Biotechnol., vol. 60:523-533 (2003); hereafter “Terpe”.
18 Livingstone et al., Protein sequence alignments: a strategy for the hierarchical analysis of residue conservation. Comput Appl Biosci. 1993 Dec;9(6):745-56. doi: 10.1093/bioinformatics/9.6.745. PMID: 8143162; hereafter “Livingstone”.
19QVQLVETGGGLVQPGGSLRLSCTASGFTFSMHAMTWYRQAPGKQRELVAVITSHGDRANYTDSVRGRFTISRDNTKNMVYLQMNSLKPEDTAVYYCNVPRYDSWGQGTQVTVSSGGLPETGGLAPAEISAVCEKGNFNVAHGLAWSYYIGYLRLILPELQARIRTYNQHYNNLLRGAVSQRLYILLPLDCGVPDNLSMADPNIRFLDKLPQQTGDRAGIKDRVYSNSIYELLENGQRAGTCVLEYATPLQTLFAMSQYSQAGFSREDRLEQAKLFCRTLEDILADAPESQNNCRLIAYQEPADDSSFSLSQEVLRHLRQEEKEEVTVGSLKTSAVPSTSTMSQEPELLISGMEKPLPLRTDFS
20 He et al., Self-assembled cGAMP-STINGΔTM signaling complex as a bioinspired platform for cGAMP delivery. Sci Adv. 2020 Jun 12;6(24):eaba7589 and Supplementary Section. doi: 10.1126/sciadv.aba7589. PMID: 32582856; PMCID: PMC7292616; hereafter “He2020”.