DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) was submitted on 7/10/2025, before the mailing of a first office action. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Status
Claims 1-15 and 19-25, filed 3/11/2024, are pending. Claims 1-15 and 19-25 are under examination.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c). Specifically, the sequences on page 23, line 5; page 23, line 33; page 24, line 12; page 24, line 25; page 24, line 35; page 25, line 12; and page 25, line 24.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because of the following informalities: the sequences on page 23, line 5; page 23, line 33; page 24, line 12; page 24, line 25; page 24, line 35; page 25, line 12; and page 25, line 24 lack sequence identifiers. Appropriate correction is required.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code at page 16, line 10; page 16, line 18. 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.
Claim Objections
Claims 1 and 4 are objected to because of the following informalities. The term “SEQ ID NO.” lack proper capitalization and punctuation. See MPEP 1.831(c): “… reference must be made to the sequence by use of the sequence identifier, preceded by "SEQ ID NO:" or the like in the text of the description or claim…” Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2, 3, and 4 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 2, claim 2 depends from claim 1. According to the specification, SEQ ID NO: 1 does not comprise an N-terminal signal sequence, so this claim becomes indefinite in the case where claim 1 is interpreted under “consisting of”.
As currently claimed, claim 1 may be interpreted under “comprising”. To clarify that this is the interpretation that claim 2 must exist under, it would be better for claim to recite: “…wherein the fusion protein does not further comprise an N-terminal signal sequence.”
Consequently, claim 2 is currently indefinite and rejected.
Regarding claim 3, claim 3 depends from claim 1. As currently claimed, claim 1 may be interpreted under “consisting of”, which means adding a further N-terminal signal sequence is prohibited under that interpretation. It is not clear which transition phrase is to be used with claim 3, therefore, claim 3 is indefinite and rejected.
Regarding claim 4, claim 4 depends from claim 3. As currently claimed, claim 1 may be interpreted under “consisting of”, which means adding a further N-terminal signal sequence is prohibited under that interpretation. It is not clear which transition phrase is to be used with claim 4, therefore, claim 4 is indefinite and rejected.
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 1-15 and 19-25 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.
Regarding claim 1, claim 1 recites a fusion protein comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ. ID NO: 1. This genus of fusion proteins is open-ended in size because of the “comprising” transition phrase and therefore encompasses an infinite sequence space.
In this case, the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. (MPEP § 2163 (II.A.3.a.ii.))
According to MPEP § 2163 (II.A.3.a.ii.), a "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014).
As described above, claim 1 recites an activity for an extremely large (open-ended) genus of fusion proteins.
MPEP § 2163 (II.A.3.a.ii.) states that “for inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’”
Even when several species are disclosed, these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, as here, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. Since each genus recited in the instant claims is large, it would be very challenging to describe sufficient species to cover the structures of the entire genus.
In the instant case, Applicant reduces 3 fusion proteins to practice. Importantly, these fusion proteins all have the same core, namely SEQ ID NO:1, with the two additional fusion proteins having N-terminal extensions. At the time the invention was made, the level of skill for preparing fusion proteins with desired functional properties was high. However, even if a synthesis and selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identify peptides that yield polypeptides with the recited properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010); see also Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1876 (Fed. Cir. 2011) (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”) Absent the conserved structure (length) provided by the provided species, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what polypeptide with a particular set of properties would look like structurally.
Applicant discloses SEQ ID NOs: 1-3. As noted above, these fusion proteins are all built around SEQ ID NO: 1. Therefore, the provided examples only represent a limited structural diversity.
Since only a limited number of species of fusion proteins are taught within the claimed genus above, the instant claim above fails the written description requirement. A representative number of species has not been taught to describe this genus. Regarding the peptides, a single point mutation can change the biophysical properties of a peptide: “In summary, we have shown that the structural changes in the fibrillar state of the Aβ42 peptide that are observed to occur upon introduction of single point mutations can be accompanied by changes in the dominance of the microscopic processes by which these aggregates are themselves formed.” (Bolognesi et al. ACS Chem Bio 9:2 (2013) page 381 col. 2 para. 3) and “In summary, while ovispirin-1 and novispirin G-10 both had solution structures that were helical and amphipathic in the presence of TFE, a relatively simple change in their primary structure (a single glycine–isoleucine exchange) had profound effects on their respective toxicities for human erythrocytes and epithelial cells.” (Sawai et al. Protein Eng. 15:3 (2002) page 232 col. 1 para. 3).
Furthermore, many sequences allowed by the current scope of the claims, result in non-functional aggregates. Wang (Wang, et al. MAbs. Vol. 1. No. 3. Taylor & Francis, (2009)) discloses a variety of aggregation prone motifs that occur in commercial antibodies (Wang, page 262, Table 2). The scope of the claims currently may incorporate such motifs and result in non-functional aggregates.
Given this unpredictability of protein design, the skilled artisan would not have been in possession of the substantial repertoire of peptide species encompassed by the claimed invention; one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genus of every polynucleotide molecule recited by claim 1. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus. Therefore, claim 1 is rejected.
Regarding claim 2, claim 1 is rejected as described above. Claim 2 fails to sufficiently limit the size of the claimed genus. Consequently, the specification fails to disclose a representative number of species to describe the claimed genus and claim 2 is rejected.
Regarding claim 3, claim 1 is rejected as described above. Claim 3 fails to sufficiently limit the size of the claimed genus. Consequently, the specification fails to disclose a representative number of species to describe the claimed genus and claim 3 is rejected.
Regarding claim 4, claim 3 is rejected as described above. Claim 4 also uses the “comprising” transition phrase and therefore the specification fails to disclose a representative number of species to describe the claimed genus and claim 4 is rejected.
Regarding claims 5-15 and 19-25, none of these claims sufficiently limit the size of the claimed genus. Consequently, the specification fails to disclose a representative number of species to describe the claimed genus in these claims and claims 5-15 and 19-25 are rejected.
A representative number of species exists for the case wherein the sequences SEQ ID NO:1, SEQ ID NO: 2, and SEQ ID NO: 3 are claimed with a “consists of” transition phrase.
Claims 5-7 and 12-14 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for KRAS-mutated cancers, cancers wherein ROCK is inhibited independently of KRAS, and non-cancerous diseases that respond to TRAIL/TRAIL-Receptor interaction disruption, does not reasonably provide enablement for treating all possible diseases. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is "reasonable" or is "undue." Consistent with Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Wands factors continue to provide a framework for assessing enablement in a utility application or patent, regardless of technology area. Guidelines for Assessing Enablement in Utility Applications and Patents in View of the Supreme Court Decision in Amgen Inc. et al. v. Sanofi et al., 89 FR 1563 (January 10, 2024). These factors include, but are not limited to:
(A) The breadth of the claims;
Claim 5 refers to the treatment of any possible disease, so this claim is quite broad.
(B) The nature of the invention;
The invention is a fusion protein that disrupts the TRAIL/TRAIL-Receptor interaction, thereby treating conditions wherein the TRAIL pathway has been hijacked by a disease state.
(C) The state of the prior art;
This therapeutic approach is known in the prior art.. KRAS-mutated cancers are known to possess misregulated TRAIL pathways and said TRAIL pathways are a therapeutic target von Karstedt et al. (von Karstedt, et al. Cell death discovery 6.1: 14 (2020)). Specifically, von Karstedt concludes that: “Whereas KRAS-mutated tumors are more resistant to induction of apoptosis by ectopically added TRAIL, they engage the
endogenous TRAIL–TRAIL-R system in disease progression. In addition, the survival of activated CD8 T cells is regulated via TRAIL–TRAIL-R. We conclude that inhibiting
endogenous TRAIL in KRAS-mutated cancers may not only inhibit tumor growth, invasion, and metastasis, but also enhance adaptive immunity against these cancers.” (von Kardstedt et al., page 6, col. 2, para. 2).
WO 2015/001345 (published 1/8/2015) discusses another case wherein ROCK is inhibited independently of KRAS, which also results in an anomalous TRAIL pathway. Finally, TRAIL has been connected to non-cancerous disease states, such as pulmonary hypertension by Hameed et al. (Hameed, et al. Journal of Experimental Medicine 209.11: 1919-1935 (2012)). Consequently there are three distinct disease groups where TRAIL/TRAIL-Receptor interaction disruption can be of benefit to a patient: KRAS-mutated cancers, cancers wherein ROCK is inhibited independently of KRAS, and non-cancerous diseases that respond to TRAIL/TRAIL-Receptor interaction disruption.
(D) The level of one of ordinary skill;
A person of ordinary skill in the art in the field of fusion proteins is usually at least a Master’s level education.
(E) The level of predictability in the art;
Protein-protein interactions are generally unpredictable. This can be improved with large data sets and usage of algorithms such as Alpha Fold.
(F) The amount of direction provided by the inventor and the existence of working examples;
Applicant provides a core sequence: SEQ ID NO: 1 and two sequences with N-terminal extensions: SEQ ID NO: 2 and SEQ ID NO 3.
(G) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
A tremendous amount of experimentation would be required to check the efficacy of these fusion proteins against diseases not known or understood to respond to TRAIL/TRAIL-Receptor interaction disruption.
The prior art referenced above makes it clear that TRAIL/TRAIL-Receptor interaction disruption is a fully enabled strategy for KRAS-mutated cancers, cancers wherein ROCK is inhibited independently of KRAS, and non-cancerous diseases that respond to TRAIL/TRAIL-Receptor interaction disruption. However, no evidence exists that this strategy is effect for all diseases in a general sense. Consequently, claim 5 is rejected.
Regarding claim 6, claim 5 is rejected as described above. Claim 6 does not sufficiently narrow claim scope to the established enabled subject material above. Consequently, claim 6 is also rejected.
Regarding claim 7, claim 5 is rejected as described above. Claim 7 does not sufficiently narrow claim scope to the established enabled subject material above. Not all cancers are known in the art to respond to the TRAIL/TRAIL-Receptor interaction disruption strategy. Consequently, claim 7 is also rejected.
Regarding claim 12, claim 7 is rejected as described above. Claim 12 does not sufficiently narrow claim scope to the established enabled subject material above. Not all cancers are known in the art to respond to the TRAIL/TRAIL-Receptor interaction disruption strategy. Consequently, claim 12 is also rejected.
Regarding claim 13, claim 7 is rejected as described above. Claim 13 does not sufficiently narrow claim scope to the established enabled subject material above. Not all cancers are known in the art to respond to the TRAIL/TRAIL-Receptor interaction disruption strategy. Consequently, claim 13 is also rejected.
Regarding claim 14, claim 7 is rejected as described above. Claim 14 does not sufficiently narrow claim scope to the established enabled subject material above. Not all cancers are known in the art to respond to the TRAIL/TRAIL-Receptor interaction disruption strategy. Consequently, claim 14 is also rejected.
Closest Prior Art
WO2015001345 discloses a fusion protein (SEQ ID NO: 15) with 99.5% identity to SEQ ID NO: 1 of the present invention. The difference is the deletion of a cysteine in the overlap region of the fusion protein. SEQ ID NO: 15 of WO2015001345 is shown starting at Val 198 to Pro 220:
... VTSSPGTPAS [C] DKTHTCPPCPAP...
This particular cysteine is not acknowledged as having any special function or structure significance in the prior art. Consequently, it not be obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to select that particular cysteine for deletion and have a reasonable expectation of a beneficial effect.
Conclusion
No claim is allowed.
Claims 1 and 4 are objected to.
Claims 1-15 and 19-25 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to David Paul Bowles whose telephone number is (571)272-0919. The examiner can normally be reached Monday-Friday 8:30-5:00.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko Garyu can be reached on (571) 270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DAVID PAUL BOWLES/Examiner, Art Unit 1654
/LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654