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 statements (IDS) submitted on 7/29/2024 and 10/24/2025 were filed before the mailing date of a first office action. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Status
The claims under examination were submitted 4/24/2024. Claims 1-13 are under examination.
Claim Interpretation
The phrase “analogue of Ezrin peptide 1 of the formula (I)” in claims 1 and 11 are interpreted to mean “analogue of Ezrin peptide 1 comprising the formula (I)”. This is primarily due to the fact that this is an analogue of a peptide that has already been claimed with comprising language.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-13 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 method of treating post COVID-19 syndrome in a subject, comprising administering to the subject a compound selected from the group consisting of Ezrin peptide 1 comprising the amino acid sequence NH2_TEKKRRETVEREKE_COOH. This claim encompasses administering an Ezrin 1 peptide 1 that can be of any length and amino acid composition that includes the sequence TEKKRRETVEREKE.
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).
Claim 1 contains no limitations on the administered peptide beyond the amino acid sequence TEKKRRETVEREKE. This is an extremely broad claim in general, and the peptides claimed here cannot be readily computed.
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 one peptide to practice and discloses an analogue of this peptide. At the time the invention was made, the level of skill for preparing and screening polypeptides 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 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 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 the usage of peptides SEQ ID NO: 1 in the context of human subject administration. The administered peptide is only 14 residues in size, whereas the claim encompasses any conceivable length polypeptide that contains those 14 residues.
The provided examples only represent a limited structural diversity. Since only a limited number of species of pharmaceutical compositions 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, filed with IDS dated 10/24/2024) 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, filed with IDS dated 10/24/2024).
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) , filed with IDS dated 10/24/2024) discloses a variety of aggregation prone motifs that occur in commercial antibodies (Wang, page 262, Table 2, filed with IDS dated 10/24/2024). 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 peptide 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 claims 2-11 and 13, claim 1 is rejected as described above. These claims dependent from claim 1, and none of these claims reduce the size of the genus claimed and therefore are rejected.
Regarding claim 11, the scope of this claim is fundamentally identical to that of claim 1 due to the current interpretation of claim 11 having a meaning of “comprising”. Because of this similarity, all the analysis regarding claim 1 applies to claim 11. 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 peptide molecule recited by claim 11. 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 11 is rejected.
Regarding claim 12, claim 11 is rejected as described above. This claim is dependent from claim 11, and none of these claims reduce the size of the genus claimed and therefore are rejected.
Claims 1-13 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 peptides 14 residues in length with a core sequence of EKKRRETVERE, does not reasonably provide enablement peptides of any conceivable length or composition. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
MPEP 2164.01(a) states: “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.’”
These factors include, but are not limited to:
The breadth of the claims
The claims are extremely broad. Claim 1 encompasses peptides of any length and any sequence that contains TEKKRRETVEREKE.
The nature of the invention
The invention is a method of treating post COVID-19 syndrome with a peptide that comprises TEKKRRETVEREKE.
The state of the prior art
The peptide TEKKRRETVEREKE was developed by Holms et al. (WO 95/33768, published 12/14/1995, filed with IDS dated 7/29/2024) as a treatment for AIDS. This disclosure does not provide any insight that would lead one of ordinary skill in the art to use this peptide for COVID-19 treatment. Holms (Immuno 2.2: 260-282. (2022), filed with IDS dated 10/24/2024) describes a possible mechanism of the claimed peptide against COVID-19: “Intravenous-VIP and spray-inhaled Human Ezrin Peptides appear to stop COVID-19 by related mechanisms of action. Human Ezrin Peptides (HEPs) such as HEP-1 and RepG3, and Vaso-active-Intestinal Peptide (VIP), appear to have a related anti-inflammatory and anti-COVID-19 activity by triggering PKA>CREB activation and inhibiting NFκB-mediated pro-inflammatory cytokine expression. However, this mechanism is still speculative and much more work needs to be done.” (Holms, Immuno (2022), page 278, para. 4, filed with IDS dated 10/24/2024) This mechanism is not conclusive nor does this qualify as prior art against this application.
Millet et al. (PLoS One 7.11: e49566 (2012) , filed with IDS dated 7/29/2024) describes how some regions of the Ezrin protein interact with SARS Coronavirus spike proteins, but this disclosure focuses on the FERM domain of the Ezrin protein: “The fact that the replication level measured by qRT-PCR was slightly lower in the clone expressing the FERM domain of ezrin than control cells at 24 hours post-infection (Fig. 7B) suggests that although ezrin restricts the rate of infection at early time points, its function may be important for later stages. The presently claimed method utilizes a peptide whose sequence is not from the FERM domain of Ezrin.” (Millet et al., page 9, col. 2, para. 3, filed with IDS dated 7/29/2024).
The level of one of ordinary skill
One of ordinary skill in the art is high; typically, a master’s level education or higher.
The level of predictability in the art
The predictability for peptides is low in general due to factors such as effects from point mutations and aggregation as described by Bolognesi et al., Sawai et al, and Wang et al above.
The amount of direction provided by the inventor
The production and administration of the disclosed peptides are well-known in the art. However, no guidance is provided for sequences significantly larger than 14 residues is provided.
The existence of working examples; and the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Applicant provides an example using a single peptide TEKKRRETVEREKE administered to several subjects. This peptide is certainly enabled. However, the current claims encompass much larger structures with additional unpredictable results. The open-ended nature of the claims would create a tremendous amount of experimentation to make and test all encompassed peptides.
Regarding claim 1, this claim recites a method using a peptide of open-ended size. As described above in the Wands analysis, such a large genus would require undue experimentation to make and test. As the peptide length grows is size, additional factors such as aggregation described by Wang et al. become increasingly problematic. This is in addition considerations such as the peptide folding back on itself and blocking the critical residues’ function. Consequently, claim 1 is rejected.
Regarding claims 2-11 and 13, claim 1 is rejected above. None of these claims substantially reduce the amount of experimentation needed, and therefore are rejected.
Regarding claim 11, this claim has approximately the same amount of experimentation needed as claim 1. Therefore, this claim is rejected for the same reasons as claim 1.
Regarding claims 12, claim 11 is rejected above. None of these claims substantially reduce the amount of experimentation needed, and therefore are rejected.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-19 of copending Application No. 17/915,847 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims anticipate the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Reference claim 1 recites a method of treating COVID-19 or post COVID-19 syndrome in a subject, comprising administering to the subject Ezrin peptide 1, wherein the Ezrin peptide 1 comprises consists of the amino acid sequence NH2_Thr-Glu-Lys-Lys-Arg-Arg-Glu-Thr-Val- Glu-Arg-Glu-Lys-Glu-COOH (SEQ ID NO: 1). Reference Claim 10 recites a method of treating COVID-19 or post COVID-19 syndrome in a subject, comprising administering to the subject an analogue of Ezrin peptide 1, wherein the analogue consists of the formula (I) NH2_X1-Glu-Lys-Lys-Arg-Arg-Glu-Thr-Val-Glu-Arg-Glu-X2-X3_COOH (SEQ ID NO. 5) (I) where X1, X2 and X3 are identical or different and are non-polar amino acid residues. Therefore, the reference claims anticipate instant claim 1.
Reference claim 10 recites a method of treating COVID-19 or post COVID-19 syndrome in a subject, comprising administering to the subject an analogue of Ezrin peptide 1, wherein the analogue consists of the formula (I) NH2_X1-Glu-Lys-Lys-Arg-Arg-Glu-Thr-Val-Glu-Arg-Glu-X2-X3_COOH (SEQ ID NO. 5) (I) where X1, X2 and X3 are identical or different and are non-polar amino acid residues. Reference Claim 18 requires the analogue of Ezrin peptide 1 is administered in a pharmaceutical composition comprising [[an]] the analogue of Ezrin peptide 1, or a combination thereof with Ezrin peptide 1, and a pharmaceutically acceptable carrier for use in a method of treating COVID-19 or post COVID-19 syndrome. Therefore, the reference claims anticipate instant claim 11.
Regarding claim 2, reference claim 3 recites saline solution for subcutaneous administration.
Regarding claim 3, reference claim 4 recites formulated for oral administration.
Regarding claim 4, reference claim 5 recites formulated for inhalation or for intranasal administration.
Regarding claims 6 and 7, reference specifies Ezrin peptide1 and its analogues are administered to an adult human in an amount of at least 0.1 mg per day, in particular at least 0.2 mg per day, e.g. in an amount of at least 0.5 mg per day, such as 0.1 to 50 mg per day or 0.2 to 20 mg per day or 0.5 to 10 mg per day.
In one embodiment, the Ezrin peptide1 is administered in a dosage in the range of or between about 0.2 and 8 milligrams (mg), preferably 1 to 5 mg, more preferably 2 to 4 mg per day. In another embodiment, the Ezrin peptide1 is administered in a dosage
in the range of 0.1 and 5 milligrams per day (mg/d), preferably 0.1 to 4 mg/d, more preferably 0.1 to 1 mg/d, especially 0.1 to 0.5 mg/d. It is also possible to start with higher dosage of e.g. in the range of 1 to 5 mg/d, more preferably 1 to 3 mg/d and then continue with lower dosage of e.g. 0.1 to 0.5 mg/d.
Regarding claims 8 and 9, reference claims 1 recites the Ezrin peptide 1 consists of the amino acid sequence NH2_Thr-Glu-Lys-Lys-Arg-Arg-Glu-Thr-Val- Glu-Arg-Glu-Lys-Glu-COOH (SEQ ID NO: 1).
Regarding claim 10, reference claim 17 recites the analogue of Ezrin peptide 1 is used in combination with Ezrin peptide 1.
Regarding claim 12, reference claim 9 recites the composition is formulated either for subcutaneous administration, oral administration, inhalation or intranasal administration.
Regarding claim 13, reference claim 19 recites X1, X2 and X3 are each individually selected from the group of amino acid residues consisting of glycine, alanine, valine, leucine, methionine, isoleucine, proline, phenylalanine, and tryptophan.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KOYELI BANERJEE whose telephone number is (571)272-5751. The examiner can normally be reached Monday-Friday 8-4PM.
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/KOYELI BANERJEE/Examiner, Art Unit 1658
/LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654