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 .
Election/Restrictions
Applicant’s election of Group II, claims 38, 47, and 50-61, in the reply filed on 2/4/2026 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)).
Applicant failed to elect a species as set forth in the Restriction Requirement. However, upon search and examination, the search was expanded to include all species of coronavirus, as listed in claim 52; all infection symptom species, as listed in claim 47; and all underlying chronic conditions/patient populations, as listed in claim 60.
Claim Status
Claims 38, 47, and 50-61 are pending. Claims 1-37, 39-46, and 48-49 have been cancelled by the Applicant.
Priority
The instant application is the 371 national stage entry of PCT/CA21/51422, filed 10/8/2021, which claims priority to the provisional application 63/089,584, filed 10/9/2020. The priority date of 10/9/2020 is acknowledged.
Information Disclosure Statement
The IDS’s filed on 4/10/2023 and 10/31/2025 are under consideration.
Drawings
The drawings are objected to because Figures 1 and 6 and their corresponding legends refer to a number of different residues/structural features based upon color but the images are in grayscale. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," 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 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) 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") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) 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 of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
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.
Pg 15 and 16 of the specification include sequences without SEQ ID NO’s
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
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 incorporation-by-reference paragraph, 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 it contains an embedded hyperlink and/or other form of browser-executable code (see Pg 12, “Sequence identity is used to” paragraph and Pg 16, paragraph under codon optimized sequence). 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.
The use of the term CellTiterGlo (Pg 16, last paragraph before results section), 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 Interpretation
The polypeptide annexin A5 is being interpreted as the same as annexin V or annexin 5, as evidenced by UniProt (UniProt ID P08758, “Annexin A5”, 2026, accessed 3/12/2026 – see Names & Taxonomy section, Pg 2).
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 47, 58, 60, and 61 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 claims 47, 58, 60, and 61, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). More specifically, see line 2 of claim 47; line 2 of claim 58; line 2 of claim 60, and lines 2 and 4 of claim 61.
Additionally, regarding claim 61: A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 61 recites the broad recitation “from about 0.001 to 10ug/ml”, and the claim also recites “0.1 to 1ug/ml” which is the narrower statement of the range/limitation. Claim 61 also recites the broad limitation “4 or more times daily” and “once daily” as well as “six times weekly” and “once weekly”.
The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Additionally, claim 61 also recites the limitation “upon appearance of symptoms”. This limitation also makes the scope of claim 61 indefinite as it is unclear what symptoms need to appear in order to practice the instantly claimed method. For purposes of examination, the limitation is being interpreted as any symptom associated with any ACE2-mediated infection.
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.
Claims 38 and 47 are 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. Claims 38 and 47 ultimately both depend from claim 50, which numerically comes after them. 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.
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.
First rejection – written description
Claims 38, 47, 50-52, 54, 55, and 58-61 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.
The claims are drawn to a method of treating an ACE2-mediated infection in a subject in need thereof by administering annexin A5. The instant specification provides written description support for administration of human annexin A5 (SEQ ID NO: 1). However the above claims do not limit the source/organism from which annexin A5 is derived from, and there are multiple proteins from multiple different sources/organism referred to as annexin A5 that display different amino acid sequences. Therefore, the limitation “annexin A5” does not disclose sufficient structure-function relationship to meet the written description requirement.
The instant specification teaches that that annexin A5 blocks SARS-CoV-2 from binding
to ACE2 and entering cells (Pg 17, Example 4; Figure 3, 4, and 6). The state of the art indicates that relying on computational methods to predict protein-protein interactions without corresponding experimental confirmation is inconsistent at best (Lowe, Not AlphaFold’s Fault, 2022; after Applicant’s priority date). Lowe teaches that there’s no guarantee that protein interaction predictions computationally generated will be accurate as they are easily influenced by the different input parameters, leading to many false positives and false negatives. Lowe indicates that, most importantly, computational predictions should be accompanied by real world experiments to confirm accuracy. In the instant application, 26 residues of annexin A5 were predicted to engage ACE2 (Figure 1F). However, whether all of these residues, or only some, are critical to annexin A5’s engagement of ACE2 is unclear and was not tested.
Additionally, not all of the predicted residues that engage ACE2 are conserved in all annexin A5 proteins. For instance, annexin A5 from the Japanese fire-bellied newt (UniProt ID P70075, “Cynops pyrrhogaster,” 2026, accessed 3/16/2025) does not have the same residues corresponding to A103 or N106 in human annexin A5. If these residues are involved in interactions with ACE2, will administering Japanese fire-bellied newt still treat ACE2-mediated infections?
Kelly et al. (US 20060058228, published 3/16/2006) discuss a phage display screen to identify peptides that distinguish between well-differentiated (HCT116) and poorly-differentiated (HT29) colon cancer cell lines. Analysis of the selected library resulted in the identification of a nine amino acid, disulfide-constrained peptide having a three amino acid (arg-pro-met, “RPM”) motif that specifically binds HT29 cells ([0032]). Substituting each of RPM with alanine significantly limited or abolished the ability of the peptide to compete with wild type RPM in a binding assay, indicating that these three residues alone accounted for the ability to bind to HT29 cells ([0034]). In contrast to this example, as stated above, it is unknown which of the 26 residues, or if all of them, engage ACE2 directly. Thus, one cannot extrapolate how even a few residue differences between human annexin A5 and other species’ annexin A5 polypeptide’s might impact functionality.
Further, Guo (H.H. Guo, J. Choe, & L.A. Loeb, Protein tolerance to random amino acid change, Proc. Natl. Acad. Sci. U.S.A. 101 (25) 9205-9210, (2004).) teaches that a protein’s tolerance to random substitutions ultimately depends on whether the residues at hand are involved the protein’s functional activity. For instance, regions that were highly substitutable in the human DNA repair enzyme 3-methyladenine DNA glycosylase (AAG) include the first 79 N-terminal residues previously demonstrated to be unnecessary for in vitro enzyme activity and DNA binding specificity. In contrast, residues that are involved in glycosylase function or DNA binding did not tolerate amino acid substitutions (“Substitutability and Structure”, Pg 9207-9209; Figure 1). Figure 1 of Guo also indicates that tolerated substitutions are generally conservative, i.e., a nonpolar residue is substituted for another nonpolar residue, etc. However, there are no explicit limitations in the instant claims regarding the sequence and/or structural similarity that other, non-human annexin A5’s must have.
Consequently, it is unknown whether all species of annexin A5 would retain the structural, chemical, and/or physical properties required to block SARS-CoV-2 from engaging ACE2. Therefore, the instant specification does not provide adequate written description to possess the broad genus described above since the specification does not disclose a correlation between the necessary structure of the sequence and the claimed function to be maintained.
Second rejection – scope of enablement
Claims 38, 47, and 50-61 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 treating an ACE2-mediate infection, does not reasonably provide enablement for preventing an ACE2-mediated infection. 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.
The Applicant’s attention is drawn to In re Wands, 8 USPQ2d 1400 (CAFC1988) at 1404 where the court set forth eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
(1) The nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
1) Nature of the invention and 5) breadth of the claims: The claims are drawn to a
method of preventing and/or treating an ACE2-mediated infection through administration of annexin A5. Prevention, as claimed, reads on administering annexin A5 to any individual with or without an ACE2-mediated infection, as prevention does not require a subject in need to have an infection. Additionally, an ACE2-mediated infection is similarly broad (see scope of enablement rejection below).
2) State of the prior art and 4) predictability or unpredictability of the art: The state of the art at the time of filing recognized ACE2 as the receptor for SARS-CoV and SARS-CoV-2 (Tay et al. The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol 20, 363–374 (2020); see Pg 365, left column, “Host cell infection and its prevention” first paragraph).
The instant specification teaches that annexin A5 blocks SARS-CoV-2 from binding to ACE2 and entering cells (Pg 17, Example 4; Figure 3, 4, and 6). However, it is unclear from the presented data whether this is a result of annexin A5 binding to ACE2, SARS-CoV-2, or both.
If, mechanistically, annexin A5 binds to SARS-CoV-2, it would be impossible to prevent a SARS-CoV-2 infection because a subject in need thereof would need to first be infected with SARS-CoV-2 in order for annexin A5 to be administered and bind to it; further, without any virus present in a subject, annexin A5 would not be able to prevent an infection as it would have nothing to bind.
If, mechanistically, annexin A5 binds to ACE2, without knowing more about the ligand-receptor dynamics between annexin A5 and ACE2, such as binding rates, as well as their physiological turnover, one cannot predict whether administration of annexin A5 to a subject without an active COVID-19 infection would successfully prevent it. Thus, in order to practice the method as claimed, one would need to continuously administer annexin A5 to the subject in need thereof to ensure the possibility of continuous binding to ACE2 and blockage of SARS-CoV-2.
3) The relative skill of those in the art: The relative skill of those in the art is high.
6) The amount of direction or guidance presented: At the time of filing, no direction or
guidance was presented in either the prior art or the instant specification that would enable one to administer annexin A5 to prevent an ACE2-mediated infections as claimed.
7) The presence or absence of working examples: The instant specification provides
no examples wherein annexin A5 is administered prior to an ACE2-mediated infection.
8) The quantity of experimentation necessary: As there are no working examples in
either the instant specification nor the prior art, reasonable guidance with respect to preventing an ACE2-mediated infection through administration annexin A5 thereof was limited. Consequently, one skilled in the art would be burdened with undue experimentation to determine the precise parameters and conditions necessary to effectively prevent an ACE2-mediated infection.
Therefore, in view of the Wands factors, as discussed above, Applicants fail to provide information sufficient to practice the claimed invention for the prevention of an ACE2-mediated infection.
Third rejection – scope of enablement
Claims 50 and 53-61 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 treating some ACE2-mediated infections, does not reasonably provide enablement for treating all ACE2-mediated infection. 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.
The Applicant’s attention is drawn to In re Wands, 8 USPQ2d 1400 (CAFC1988) at 1404 where the court set forth eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
(1) The nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
1) Nature of the invention and 5) breadth of the claims: The invention is a method of
treating an ACE2-mediated infection comprising administering to a patient in need thereof annexin A5. The above claims are written such that the breadth includes any infection mediated to any degree by ACE2, no matter how direct or how indirect.
The issue is the degree of mediation required between ACE2 and the infection, and whether infections indirectly mediated by ACE2 can be treated by practicing this method.
2) State of the prior art and 4) predictability or unpredictability of the art: The instant
specification teaches that annexin A5 can treat SARS-CoV-2 (Pg 17, Example 4; Figure 3, 4, and 6).
At the time of filing, the art recognized that ACE2 mediates certain infections, but not all
Infections, are mediated directly by ACE2.
For example, Sodhi (Dynamic Variation of Pulmonary ACE2 Is Required to Modulate Neutrophilic Inflammation in Response to Pseudomonas aeruginosa Lung Infection in Mice, The Journal of Immunology, Volume 203, Issue 11, December 2019, Pages 3000–3012.) teaches ACE2 expression levels vary during P. aeruginosa lung infections, which impacts the severity of bacterial pneumonia (Abstract). Genetically deleting ACE2 or administering ACE2 inhibitors to wildtype mice resulted in exaggerated lung injury and reduced survival compared to non-deleting/inhibiting experiments, suggesting that the presence of functional ACE2 provides a protective effect against P. aeruginosa. This notion is further supported by subsequent experiments in which recombinant ACE2 was administered to mice prior to and after P. aeruginosa infection also resulted in exaggerated lung injury and reduced survival. Sodhi ultimately concludes that ACE2 contributes to the pathogenesis of bacterial pneumonia driven by P. aeruginosa through modulating neutrophil infiltration and lung inflammation; in other words, ACE2 indirectly mediates P. aeruginosa infections.
Similarly, Zhou (Angiotensin-converting enzyme 2 protects from lethal avian influenza A H5N1 infections. Nat Commun. 2014 May 6;5:3594.) reports that ACE2 knockout mice die significantly faster than wild-type controls when challenged with live H5N1 avian flu viruses, also suggesting that ACE2 exhibits a protective effect against H5N1 but does not mediate its entry into cells directly.
The instant application teaches that annexin A5 interacts directly with ACE2, thereby preventing SARS-CoV-2 from engaging ACE2 and entering cells. However, the above cited studies indicate that genetic loss or pharmacological inhibition of ACE2 prior to infection results in worse infection symptoms, suggesting that ACE2 likely provides a protective effect against several of the infective agents but does not directly mediate said infective agents entering cells. Therefore, one skilled in the art would predict that the mechanism of action of annexin A5 as described in the instant application would be incapable of treating these ACE2-mediated infections.
3) The relative skill of those in the art: The relative skill of those in the art is high.
6) The amount of direction or guidance presented: At the time of filing, no direction or
guidance was presented in either the prior art or the instant specification that would enable one to administer annexin A5 to treat the breadth of ACE2-mediated infections as claimed.
7) The presence or absence of working examples: The instant specification provides
only a few examples wherein annexin A5 is administered to cells in culture infected with SARS-CoV-2 but no examples wherein a subject is treated with annexin A5.
8) The quantity of experimentation necessary: As no working examples wherein a
subject is treated are disclosed in the instant specification and only a few in the prior art, reasonable guidance with respect to treating an ACE2-mediated infection comprising administering annexin A5 thereof was limited. Consequently, one skilled in the art would be burdened with undue experimentation to determine the precise parameters and conditions necessary to effectively treat all ACE2-mediated infections.
Therefore, in view of the Wands factors, as discussed above, Applicants fail to provide information sufficient to practice the claimed invention for the treatment of all ACE2-mediated infections.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
First rejection
Claim(s) 38, 47, and 50-57 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by London (Screen captures from YouTube video clip entitled "London: Studying a Human Protein in the Treatment of Critically Ill COVID-19 Patients," 4 pages, uploaded on May 26, 2020 by user "Rogers tv". Retrieved from Internet: <https://www.youtube.com/watch?v=MWZEayu8U08>), as evidenced by UniProt (UniProt ID P08758, “Annexin A5”, 2026, accessed 3/12/2026).
Regarding claims 38 and 50-52, London discloses a method of treating COVID-19 with annexin A5 (Pg 1, description of video, bottom gray box). Per the instant specification, COVID19 is caused by the coronavirus SARS-CoV-2 (see instant specification, Pg 1, first sentence in Background).
Regarding claim 47, London further discloses that the method is used for patients with sepsis (Pg 1, description of video, bottom gray box; Pg 2, timestamp 0:22).
Regarding claims 53 and 54, London discloses that annexin A5 is a recombinant human protein (timestamp 0:41; Pg 3).
Regarding claims 55-57, human annexin A5 exhibits 100% identity to the instant SEQ ID NO: 1, as evidenced by UniProt (“Sequence,” Pg 8).
Second rejection
Claim(s) 38, 47, 50-53, and 55-57 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by “Provincial” (“Provincial funding enables coronavirus research in London, Ontario; May 26, 2020; retrieved from https://www.sjhc.london.on.ca/research/media-releases/provincial-funding-enables-coronavirus-research-london-ontario; accessed 3/12/2026), as evidenced by UniProt (UniProt ID P08758, “Annexin A5”, 2026, accessed 3/12/2026).
Regarding claims 38 and 50-52, Provincial discloses a method of treating COVID-19 with annexin A5 (“Studying a human protein in the treatment of critically ill COVID-19 patients”, first paragraph). Per the instant specification, COVID19 is caused by the coronavirus SARS-CoV-2 (see instant specification, Pg 1, first sentence in Background).
Regarding claim 47, Provincial further discloses that the method is used for patients with sepsis, ARDS, and multi-organ failure (“Studying a human protein in the treatment of critically ill COVID-19 patients”, first and second paragraphs).
Regarding claims 53, Provincial discloses that the annexin A5 is a human protein (“Studying a human protein in the treatment of critically ill COVID-19 patients”, 4th paragraph).
Regarding claims 55-57, human annexin A5 exhibits 100% identity to the instant SEQ ID NO: 1, as evidenced by UniProt (“Sequence,” Pg 8).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
First rejection
Claim(s) 38, 47, and 50-59 are rejected under 35 U.S.C. 103 as being unpatentable over London (Screen captures from YouTube video clip entitled "London: Studying a Human Protein in the Treatment of Critically Ill COVID-19 Patients," 4 pages, uploaded on May 26, 2020 by user "Rogers tv". Retrieved from Internet: <https://www.youtube.com/watch?v=MWZEayu8U08>) in view of JP 2004535375 A (“JP2004”, published 11/25/2004; reference cited in prior Restriction Requirement).
The teachings of London have been set forth above. London does not teach binding annexin A5 to a moiety, such as a therapeutic, detectable, and/or targeting agent.
JP2004 teaches methods and compositions for imaging cell death in vivo (Abstract). JP2004 teaches that annexin V is commonly found in large amounts in the cytoplasm of many cells, and annexins have properties that make them useful as diagnostic and/or therapeutic agents, such as high affinity for membrane layers expressing phosphatidylserine (PS), which typically indicates apoptosis and/or necrosis ([0010-0011]).
JP2004 further teaches that combining annexin and a contrast agent allows for efficient and effective detection of dying cells using MRI. Annexins can also be combined with optically active molecules, such as fluorescent dyes, which allows efficient and effective detection of dying cells by optical imaging. Annexins can also be conjugated to therapeutic radioisotopes ([0012]).
In summary, London teaches a method of treating COVID-19 comprising administering annexin A5 to a subject in need thereof. JP2004 teaches conjugating detectable and/or therapeutic agents to annexin V as a means to image and detect dying cells in vivo. Therefore, regarding claim 58, it would be prima facie obvious to treat individuals with COVID-19 with annexin V conjugates taught by JP2004. One skilled in the art would be motivated to do so in order to evaluate the severity of cell death during a COVID-19 infection in a subject in need thereof and/or further treat COVID-19 through administration of annexin V conjugated to a therapeutic compound as described. One would have a reasonable expectation of success as JP2004 established that annexin V could be conjugated to such moieties, and London established a method of treating comprising administering annexin V.
Regarding claim 59, JP2004 teaches that the conjugates can be administered intranasally or through respiratory tract routes (reads on inhalation; [0032]).
Claim(s) 38, 47, 50-57 and 60 are rejected under 35 U.S.C. 103 as being unpatentable over London (Screen captures from YouTube video clip entitled "London: Studying a Human Protein in the Treatment of Critically Ill COVID-19 Patients," 4 pages, uploaded on May 26, 2020 by user "Rogers tv". Retrieved from Internet: <https://www.youtube.com/watch?v=MWZEayu8U08>) in view of Fang et al. (Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med. 2020 Apr;8(4):e21. doi: 10.1016/S2213-2600(20)30116-8. Epub 2020 Mar 11. Erratum in: Lancet Respir Med. 2020 Jun;8(6):e54.).
The teachings of London have been set forth above. London does not teach treating COVID-19 wherein the subject has a chronic condition such as hypertension or diabetes.
Fang teaches that many observational studies conducted during the early days of the COVID-19 pandemic noted that a substantial number of ICU patients had chronic conditions such as hypertension and/or diabetes. Fang also notes that these comorbidities are often treated with ACE inhibitors, which, when taken, result in increased expression of ACE2 (Pg 2, first column, first paragraph – second column, first paragraph). Therefore, there is the potential that individuals with hypertension and/or diabetes who take ACE inhibitors will have an increased risk of developing COVID-19 (Second column, second and third paragraphs).
In summary, London teaches a method of treating COVID-19 comprising administering annexin A5 to a subject in need thereof. Fang teaches that individuals who have hypertension or diabetes and/or take ACE inhibitors are more likely to be susceptible to COVID-19. Therefore, regarding claim 60, it would be prima facie obvious to treat individuals with hypertension or diabetes and/or take ACE inhibitors using the method taught by London. One skilled in the art would be motivated to do so in order to effectively treat those with increased susceptibility. One would have a reasonable expectation of success as London teaches effectively treating COVID-19 subjects with increased risk of other comorbidities (i.e., sepsis).
Claim(s) 38, 47, 50-57, and 61 are rejected under 35 U.S.C. 103 as being unpatentable over London (Screen captures from YouTube video clip entitled "London: Studying a Human Protein in the Treatment of Critically Ill COVID-19 Patients," 4 pages, uploaded on May 26, 2020 by user "Rogers tv". Retrieved from Internet: <https://www.youtube.com/watch?v=MWZEayu8U08>) in view of Le Tourneau et al. (Dose escalation methods in phase I cancer clinical trials. J Natl Cancer Inst. 2009 May 20;101(10):708-20.).
The teachings of London have been set forth above. In addition, London also teaches that COVID19 patients are administered annexin A5 twice a day for 7 days by intravenous infusion (Pg 4; timestamp 2:06). London does not teach the dosage at which annexin A5 is administered.
Le Tourneau teaches dosage optimization of drugs or new combinations of drugs in phase I clinical trials for cancer (Title, Abstract). Le Tourneau explains that in rule-based phase I trials of drug combinations, the dose level of each drug may be based on several factors such as preclinical data, current disease-specific standard treatments, the expected control arm if a combination of drugs under evaluation may be benchmarked by future randomized trials, and/or empiricism (Pg 715, “Designs for trials of combinations of agents, second paragraph). All of these decisions impact the recommended schedules and dosages, which can determine the success or failure of a trial.
In summary, London teaches a method of treating COVID-19 through administration of annexin A5 to subject in need thereof twice daily for 7 days. Le Tourneau teaches dosage optimization in phase I cancer clinical trials (Title, Abstract). Le Tourneau explains that in rule-based phase I trials of drug combinations, the dose level of each drug may be based on several factors such as preclinical data, current tumor-specific standard treatments, the expected control arm if the combination of drugs under evaluation may be benchmarked by future randomized trials, and/or empiricism (Pg 715, “Designs for trials of combinations of agents, second paragraph). Bayesian modeling as well as pharmacokinetic analyses may further provide information regarding toxicities and interactions between different anticancer drugs administered in combination (third and fourth paragraphs). All of these decisions impact the recommended schedules and dosages, which can determine the success or failure of a combination.
Therefore, regarding claim 61, it would have been prima facie obvious to one of ordinary skill in the art because Le Tourneau recognized that scheduling and dosing of combinations of anticancer therapeutics depended on a number of factors, as described above. Thus, it would have been obvious to optimize the dosage schedule and dosages as claimed in order to effectively treat cancer. See MPEP 2144.05(II).
Second rejection
Claim(s) 38, 47, and 50-61 are rejected under 35 U.S.C. 103 as being unpatentable over Feng et al. (US20120014920A1, published 01/19/2012) in view of Tay et al. (The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol 20, 363–374 (2020)).
Feng teaches a composition comprising an effective amount of annexin A5 for use in treatment of an inflammatory disorder (Abstract). An inflammatory disorder is described as usually mediated by an inflammatory cytokine cascade, defined as an in vivo release from cells of at least one proinflammatory cytokine in a subject, wherein the cytokine release affects a physiological condition of the subject ([0039]). Further, a cytokine is a soluble protein or peptide which is naturally produced by mammalian cells and which act in vivo as humoral regulators at micro- to picomolar concentrations. Non-limiting examples of proinflammatory cytokines are tumor necrosis factor alpha (TNF), interleukin (IL-)Ia, I-beta, -6, -8, -18, interferon-gamma, HMG-1, platelet-activating factor (PAF), and macrophage migration inhibitory factor (MIF) ([0040]). More specifically, Feng teaches that annexin A5 treatment inhibits the proinflammatory effect of TNF.
Feng does not teach administering annexin A5 to a patient in need thereof with an ACE2-mediated infection.
Tay teaches about SARS-CoV-2 and its interactions with the immune system as well as the subsequent contribution of dysfunctional immune responses to disease progression (Abstract). Tay teaches both SARS-CoV and SARS-CoV-2 target ACE2 receptors expressed in cells such as airway epithelial cells, alveolar epithelial cells, vascular endothelial cells, and macrophages in the lung (Pg 365, left column, “Host cell infection and its prevention” first paragraph). Infection results in induced death and injury of virus-infected cells and tissues as part of the virus replicative cycle, which can cause pyroptosis and subsequent inflammatory response, leading to the production of proinflammatory molecules such asIL-6 and INFγ. In certain cases, a dysfunctional immune response occurs which triggers a cytokine storm that mediates widespread lung inflammation; such patients with severe COVID-19 exhibit higher levels of proinflammatory cytokines such as IL-6 and tumor necrosis factor (TNF; Pg 366, “Inflammation immunopathogenesis”, second paragraph – third paragraph; Figure 1).
Thus, in summary, Feng teaches a method of treating inflammatory disease through administration of annexin A5, which targets TNF as well as other proinflammatory cytokines. Tay teaches SARS-CoV-2 is an ACE-mediated viral infection that results in a release of proinflammatory cytokines such as IL-6 and TNF. Based on these teachings, regarding claims 50-51, it would be obvious to use the method taught by Feng to treat COVID-19. One skilled in the art would be motivated to do so in order to effectively treat COVID-19 infections by targeting the underlying inflammation that contribute to disease progression. One would have a reasonable expectation of success given that Feng established that annexin A5 targets proinflammatory cytokines such as TNF and IL-6, both of which are released by lung cells during a COVID-19 infection, particularly during severe cases.
Regarding claim 38 and 47, Tay teaches that ARDS is seen in severe COVID-19, which can lead to lead to respiratory failure and/or sepsis; in cases of sepsis, multi-organ lung damage can occur, especially in cardiac systems (Pg 365, left column, first and second paragraphs; Figure 1). Additionally, Feng teaches that the inflammatory disorder treated can be one where an inflammatory cytokine cascade causes a systemic reaction such as septic shock ([0045]).
Regarding claim 52, Tay teaches coronavirus species 229E, OC43, NL63, HKU1, SARS-CoV, MERS, and SARS-CoV-2 impact the upper and lower respiratory tracts to varying degrees (Pg 363, right column, “Pathogenesis of COVID-19”).
Regarding claims 53 and 54, Feng teaches administering recombinant human annexin A5 ([0120, 0128, 0132, 0133, 0140, 0143, and 0147]).
Regarding claims 55-57, Feng teaches annexin A5 can consist of SEQ ID NO: 1 or a polypeptide variant with a sequence that is at least 80% identical to a naturally-occurring form the annexin A5 polypeptide ([0095]; Sequence Listing, Col. 13, “Amino Acid Sequence for Human Annexin A5”).
Regarding claim 58, Feng teaches making an annexin A5 fusion protein further comprising a targeting polypeptide ([0110]).
Regarding claim 59, Feng teaches administration can occur intranasally or intrabronchially (reads on inhalation; [0112]).
Regarding claim 60, Feng teaches the inflammatory disorder treated can be type I diabetes ([0045]).
Regarding claim 61, Feng teaches administration of annexin A5 at 1ug/ml ([0034]; Figure 8). Feng further teaches annexin A5 can be administered as part of a routine schedule, which may involve administration of a daily basis, every 2, 3, 4, 5, 6, days or a weekly basis, monthly basis, or any set number of days or weeks between, every two months – every 12 months ([0113]).
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.
Claim 48 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-5, and 9-13 of U.S. Patent No. 9,192,649 B2 (‘649). Although the claims at issue are not identical, they are not patentably distinct from each other because they contain overlapping subject matter.
Claim 1 of US ‘649 recites a method for treatment of sepsis in a subject not having a blood coagulation disorder comprising administering an effective amount of Annexin A5 to the subject, wherein the Annexin A5 interacts with TLR4 receptors. The scope of this claim overlaps with the instant claim 48, which recites that the instant method of treating an ACE2-mediated infection is a coronavirus wherein a symptom that arises is sepsis. The scope of independent claim 9 of US ‘649 also overlaps with the instant claim 48.
Dependent claims include the species of annexin A5 (claims 3, 5, 11, 13) and the subject being treated (claim 4, 12).
Conclusion
No claim is allowed.
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/SARA E KONOPELSKI SNAVELY/Examiner, Art Unit 1658
/FRED H REYNOLDS/Primary Examiner, Art Unit 1658