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 .
DETAILED ACTION
Status of the Claims
Claims 1-4, 8-13, 17-18, and 20-28 are pending. Claims 3, and 18 have been withdrawn from further consideration as being directed towards nonelected species until a generic claim has been found allowable. Claims 1-2, 4, 8-13, 17, and 20-28 are examined on their merits.
Duplicate Claims Warning Withdrawn
Applicant has amended claims 8, 17, and 20 to no longer be identical to claims 1, 2, and 4. The duplicate claims warning over claims 8, 17, and 20 is thereby withdrawn.
Duplicate Claims Warning Necessitated by Amendment
Applicant is advised that should claims 4 be found allowable, claim 12 will be objected to under 37 CFR 1.75 as being substantial duplicates thereof.
Applicant is advised that should claim 8 be found allowable, claim 9 will be objected to under 37 CFR 1.75 as being substantial duplicates thereof.
When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
35 U.S.C. § 112(b) Rejections Maintained
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.
The rejection of claims 9-11 and 13 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 is maintained.
Applicant argues in the response filed on March 23rd 2026 that the additional limitations of claims 9-13 have been amended to articulate the claimed structure/method.
For example, claim 9 has been amended to recite:
“The method of claim 8, wherein the pharmaceutically acceptable salt of ORE-1001 that comprises the appendage obstructs viral binding by blocking access to the viral binding site on the angiotensin-converting enzyme 2 (ACE2) receptor.” As stated in the previous 112(b) rejection, it is unclear how this phrase further limits the method of treatment described. The phrase does not appear to limit the compound administered, the method of administration, the patient population receiving the compound, the amount administered, or any other aspect of the method of claim 1 other than the results of the administration (i.e. the obstruction of viral binding), which would be inherent in the administration itself. Consequently, the 112(b) rejection for claim 9 is maintained.
Claim 10 has been amended to recite that the method of claim 9 “treats or prevents the infections disease caused by the coronavirus in the subject by obstructing the virus binding.” This amendment does not address the deficiencies of the previous 112(b) rejection over claim 10 (below), but only functionally describes an intended result of the method (the obstruction of viral binding).
Similarly, claim 13 has been amended to recite intended results (the blocking of the viral binding site), but the deficiencies of the previous 112(b) rejections are never addressed.
Claim 11 remains indefinite because the term “downstream work” is never clarified (see the previous 112(b) rejection.
35 U.S.C. § 112(b) Rejections Maintained
Claim 9 is indefinite for the phrase, “wherein said ACE2 inhibitor ORE-1001 or a pharmaceutically acceptable salt thereof obstructs viral binding,” because one of ordinary skill in the art could not reasonably determine how the phrase further limits the method of claim 4. Specifically, the phrase does not appear to limit the compound administered, the method of administration, the patient population receiving the compound, the amount administered, or any other aspect of the method of claim 4 other than the results of the administration, which would be inherent in the administration itself. These results are demonstration in the specification (specification, pg. 20), but the specification provides no guidance as to how the method would need to be further limited in order to achieve said results.
Claim 10 is indefinite for the phrase, “wherein said ACE2 inhibitor ORE-1001 or a pharmaceutically acceptable salt thereof obstructs the virus’ interaction with two moderately flexible helices on the side of ACE2, to which the leucine of ORE-1001 directs towards and that comprises a suitable linker site to extend out from, and thereby to obstruct virus binding,” because one of ordinary skill in the art could not reasonably determine how the phrase further limits the method of claim 9. Specifically, the phrase does not appear to limit the compound administered, the method of administration, the patient population receiving the compound, the amount administered, or any other aspect of the method of claim 9 other than the results of the administration, which would be inherent in the administration itself. These results are demonstration in the specification (specification, pg. 20), but the specification provides no guidance as to how the method would need to be further limited in order to achieve said results.
Claim 11 is indefinite for the phrase “wherein said ACE2 inhibitor comprises a pharmaceutically acceptable salt of ORE-1001 that is a fluorophore for labeling and downstream work.” Specifically, it is unclear what is meant by the term “downstream work.” The phrase is mentioned once in the specification, on page 21, but never defined. The phrase appears to limit particular results of the administration of the ORE-1001, but it is unclear what those results are and thus it is unclear how the structure of ORE-1001 must be further limited in order to achieve said results.
Claims 12 and 13 are indefinite for the phrase, “wherein the ORE-1001 or a pharmaceutical acceptable salt thereof comprises a conjugate that is positioned to block the virus from binding to ACE2,” because one of ordinary skill in the art could not reasonably determine how the phrase further limits the methods of claims 4 and 13, respectively. Specifically, the phrase appears to limit an aspect of the compound’s structure (a conjugate of ORE-1001) based on specific results achieved (the blocking of the virus from binding to ACE2). One of ordinary skill in the art could not reasonably determine how the structure of ORE-1001 must be modified with a conjugate in order to achieve the described activity. Some conjugates are described in the specification (specification, pg. 21, Figure 4), but guidance to modify the molecule in order to achieve the specific activity described is not found.
35 U.S.C. § 112(b) Rejections Necessitated by Amendment
Claims 1-2, 4, 8-13, 17, and 20-28 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 and all of its dependent claims are indefinite for the phrase “wherein the ACE2 inhibitor further comprises an appendage, and wherein the appendage obstructs binding of the coronavirus to the viral binding site on the angiotensin-converting enzyme 2 (ACE2) receptor.”
Claim 1 recites a method of treating or preventing an infectious disease caused by coronavirus in a subject in need thereof via administration of the ACE2 inhibitor, MLN-4760 or a pharmaceutically acceptable salt thereof. Said compound is defined in its entirety by the structure:
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The phrase “wherein the ACE2 inhibitor further comprises an appendage, and wherein the appendage obstructs binding of the coronavirus to the viral binding site on the angiotensin-converting enzyme 2 (ACE2) receptor,” appears to describe a potential modification to the structure of MLN-4760. However, the extent that said modification is described in the specification is only what is shown in Figure 4, which merely describes a process of developing modified versions of MLN-4760. However, in no case is it apparent that said modified version is further limiting to MLN-4760 itself. As stated earlier, a chemical compound is defined in its entirety by its structure. As such, a complete and unique chemical compound, such as MLN-4760 cannot be ‘further limited’ by additions to its chemical structure.
Furthermore, the phrase, “wherein the ACE2 inhibitor further comprises an appendage,” does not state or even imply any particular chemical structure, but only that the chemical structure of the MLN-4760 is incomplete. Thus, one of ordinary skill in the art could not reasonably determine what it means for a compound to “comprise an appendage.”
As it is unclear how the phrase “wherein the ACE2 inhibitor further comprises an appendage, and wherein the appendage obstructs binding of the coronavirus to the viral binding site on the angiotensin-converting enzyme 2 (ACE2) receptor,” further limits the method of claim 1, claim 1 and all of its dependent claims are indefinite.
Claims 8, 12, 17, 20-26, and 28 each suffer from similar deficiencies:
Claim 8: “wherein the ACE2 inhibitor comprises a pharmaceutically acceptable salt of MLN-4760 and wherein the pharmaceutically acceptable salt comprises the appendage.”
Claim 12: “wherein the ORE-1001 conjugate or a pharmaceutically acceptable salt thereof comprises an appendage that is positioned to block the virus from binding to ACE2”
Claim 17: “wherein the ACE2 inhibitor comprises a pharmaceutically acceptable salt of MLN-4760 and wherein the pharmaceutically acceptable salt comprises the appendage.”
Claim 20: “wherein the ACE2 inhibitor comprises a pharmaceutically acceptable salt of MLN-4760 and wherein the pharmaceutically acceptable salt comprises the appendage.”
Claim 21: “wherein the ACE2 comprises an ORE-1001 conjugate that includes the appendage.”
Claim 22: “wherein the appendage comprises a heterocyclic ring moiety comprising a triazole.”
Claim 23: “wherein the heterocyclic ring moiety comprising the triazole is appended to the ORE-1001 molecule via an alkyl or (hetero)aryl moiety, R1, and wherein a substituent R2 is appended to the triazole.”
Claim 24: “wherein the R2 substituent is selected from the group consisting of biotinylated species.”
Claim 25: “wherein the appendage comprises
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wherein R1 is selected from the group consisting of an alkyl or (hetero)aryl moiety and wherein R2 is selected from the group consisting of a substituent that disrupts the ACE2-spike protein-protein interaction surface.”
Claim 26: “wherein the ORE-1001 and appendage thereto comprises the molecule having the structure:
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”
Claim 28: “wherein the appendage obstructs the virus’ interaction with two moderately flexible helices on the side of ACE2…”
In each case, the claim attempts to further limit the structure of the compound administered, which is already defined in its entirety by its chemical structure (i.e. A compound defined by the structure,
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cannot further comprise the compound,
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).
As such, all of claims 8, 12, 17, 20-26, and 28 are indefinite.
Claim 12 is further indefinite for reciting the phrase “the ORE-1001 conjugate” There is insufficient antecedent basis for this limitation in the claim.
Claims 27 is indefinite for the phrase, “wherein the ORE-1001 or a pharmaceutical acceptable salt thereof comprises a conjugate that is positioned to block the virus from binding to ACE2,” because one of ordinary skill in the art could not reasonably determine how the phrase further limits the methods of claims 4 and 13, respectively. Specifically, the phrase appears to limit an aspect of the compound’s structure (a conjugate of ORE-1001) based on specific results achieved (the blocking of the virus from binding to ACE2). One of ordinary skill in the art could not reasonably determine how the structure of ORE-1001 must be modified with a conjugate in order to achieve the described activity. Some conjugates are described in the specification (specification, pg. 21, Figure 4), but guidance to modify the molecule in order to achieve the specific activity described is not found.
35 U.S.C. § 103 Rejections Maintained
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The rejection of claims 1 and 8 under 35 U.S.C. 103 as being unpatentable over Towler (Towler et al., ACE2 X-Ray Structures Reveal a Large Hinge-bending Motion Important for Inhibitor Binding and Catalysis*, Journal of Biological Chemistry, Volume 279, Issue 17, 2004, Pages 17996-18007) is maintained.
The rejection of claims 2, 4, 9-13, 17, and 20 under 35 U.S.C. 103 as being unpatentable over Towler (Towler et al., ACE2 X-Ray Structures Reveal a Large Hinge-bending Motion Important for Inhibitor Binding and Catalysis*, Journal of Biological Chemistry, Volume 279, Issue 17, 2004, Pages 17996-18007) in view of Zhou (Zhou et al., A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270–273 (2020)) is maintained.
Applicant’s amendments and arguments in the response filed on March 23rd 2026 are acknowledged. Applicant has not argued the validity of the 103 rejections over either Towler or Towler and Zhou (i.e. that one of ordinary skill in the art would reasonably treat coronavirus infections with MLN-4760). Applicant has amended the claims to recite that the ACE2 inhibitor comprises an appendage that obstructs the coronavirus binding to the receptor. However, as it is unclear how applicant’s amendments further limit the claimed subject matter (see the above 112(b) rejections), the 103 rejections are maintained.
Regarding claims 8, 17, and 20, previously identified as being identical to claims 1, 2, and 4, the claims have been amended to be directed towards the method of claims 1, 2, and 4, respectively, wherein the ACE2 inhibitor comprises a pharmaceutically acceptable salt of the elected compound. As treatment with pharmaceutically acceptable salts of the compound would be obvious, the claims remain obvious.
As claims 9-11 have been amended to depend on claim 1, the previous 103 rejections over claims 1 and 8 are now applicable over claims 9-11.
35 U.S.C. § 103 Rejections Reiterated
Claims 1 and 8-11 are rejected under 35 U.S.C. 103 as being unpatentable over Towler (Towler et al., ACE2 X-Ray Structures Reveal a Large Hinge-bending Motion Important for Inhibitor Binding and Catalysis*, Journal of Biological Chemistry, Volume 279, Issue 17, 2004, Pages 17996-18007).
Claims 1 and 8 are directed towards a method of preventing or treating an infectious disease caused by coronavirus via administration of the angiotensin-converting enzyme 2 (ACE2) inhibitor, MLN-4760 (also known as ORE-1001),
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Towler teaches the binding of MLN4760 to ACE2 and suggests MLN-4760 for blockage of SARS coronavirus infection:
ACE2 as the SARS Coronavirus Receptor—The recent identification of ACE2 as a functional receptor for the SARS coronavirus (4, 5) has raised questions about what binding determinants on ACE2 interact with the virus. Mutations of the ACE2 zinc-coordinating residues His374 and His378 to asparagines were found to have no effect on syncytial formation (4), suggesting that interfering with the active site has no effect on viral spike protein binding to ACE2. However, the large conformational change observed upon MLN-4760 binding to ACE2 could prove to be unfavorable for viral binding to its receptor and/or syncytial formation. Thus, metallopeptidase inhibitors such as MLN-4760 may still prove useful for prevention of viral binding to ACE2 and blockage of infection.
[Towler, pg. 18006]
While Towler does not explicitly treat coronavirus infection with MLN-4760, this suggestion would motivate one of ordinary skill in the art to try such a treatment. Claims 1 and 8 are therefore prima facie obvious.
Claim 9 requires that, in the method of claim 4, ORE-1001 (another name for MLN-4760) obstructs viral binding. Towler teaches the obstruction of viral binding:
However, the large conformational change observed upon MLN-4760 binding to ACE2 could prove to be unfavorable for viral binding to its receptor and/or syncytial formation.
[Towler, pg. 18006]
Claim 9 is therefore prima facie obvious.
As it is unclear how claims 10-11 further limit the method of claim 9, they too are prima facie obvious.
Claims 2, 4, 12-13, 17, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Towler (Towler et al., ACE2 X-Ray Structures Reveal a Large Hinge-bending Motion Important for Inhibitor Binding and Catalysis*, Journal of Biological Chemistry, Volume 279, Issue 17, 2004, Pages 17996-18007) in view of Zhou (Zhou et al., A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270–273 (2020)).
Claims 2 and 4 limit the method of claim 1 to the treatment of COVID-19, a respiratory illness caused by SARS-CoV2 (referred to early-on as 2019-nCoV) infection, via administration of MLN-4760. For the teachings of Towler as they relate to the treatment of coronavirus infection with MLN-4760, see the above 103 rejection of claim 1 over Towler. Regarding the treatment of COVID-19, while Towler does not explicitly a patient population wherein the coronavirus infection results in COVID-19, one of ordinary skill in the art would have had a reasonable expectation in administering MLN-4760 to such a patient population because ACE2 was known early-on as being the cellular entry receptor responsible for accepting the SARS-CoV2 (2019-nCoV) virus. See Zhou:
ACE2 is known to be a cell receptor for SARS-CoV14. To determine whether 2019-nCoV also uses ACE2 as a cellular entry receptor, we conducted virus infectivity studies using HeLa cells that expressed or did not express ACE2 proteins from humans, Chinese horseshoe bats, civets, pigs and mice. We show that 2019-nCoV is able to use all ACE2 proteins, except for mouse ACE2, as an entry receptor to enter ACE2- expressing cells, but not cells that did not express ACE2, indicating that ACE2 is probably the cell receptor through which 2019-nCoV enters cells (Fig. 3). We also show that 2019-nCoV does not use other coronavirus receptors, such as aminopeptidase N (APN) and dipeptidyl peptidase 4 (DPP4) (Extended Data Fig. 7).
[Zhou, pg. 272]
One of ordinary skill in the art would therefore have a reasonable expectation of success in using ACE2 inhibitors, such as MLN-4760, to prevent COVID-19 infection by blocking viral entry into the cells, and claims 2 and 4 are therefore prima facie obvious.
As it is unclear how claim 12 further limits the method of claim 4, it too is prima facie obvious.
Claim 13 is directed towards a method of treating or preventing an infectious disease caused by COVID-19 via administration of (S,S)-2-[1-carboxy-2-[3-(3,5-dichlorobenzyl)-3H-imidazol-4-yl]-ethylaminol-4-methylpentanoic acid (MLN-4760) wherein the compound comprises a conjugate that is positioned to block the virus from binding to ACE2. For the teachings of Towler and Zhou as they are relevant to the treatment of COVID-19 with MLN-4760, see the above 103 rejection for claim 4. Regarding the phrase, “wherein the (S,S)-2-[1-carboxy-2-[3-(3,5-dichlorobenzyl)-3H-imidazol-4-yl]-ethylaminol-4-methylpentanoic acid, or a pharmaceutically acceptable salt thereof comprises a conjugate that is positioned to block the virus from binding to ACE2,” it is unclear how the phrase further limits the method of claim 13 (see the above 112(b) rejection for claim 13). Claim 13 is therefore prima facie obvious.
35 U.S.C. § 103 Rejections Necessitated by Amendment
Claims 21-26 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Towler (Towler et al., ACE2 X-Ray Structures Reveal a Large Hinge-bending Motion Important for Inhibitor Binding and Catalysis*, Journal of Biological Chemistry, Volume 279, Issue 17, 2004, Pages 17996-18007).
Claim 21 is directed towards the method of claim 1 wherein the ACE2 inhibitor comprises an ORE-1001 conjugate that includes the appendage. As it is unclear how claim 21 further limits the method of claim 1 (see the above 112(b) rejection for claim 21), claim 21 is prima facie obvious for the same reasons as claim 1.
Claims 22-26 are directed towards:
The method of claim 21, wherein the appendage comprises a heterocyclic ring moiety comprising a triazole
The method of claim 22, wherein the heterocyclic ring moiety comprising the triazole is appended to the ORE-1001 molecule via an alkyl or (hetero)aryl moiety, R1, and wherein a substituent R2 is appended to the triazole
The method of claim 23, wherein the R2 substituent is selected from the group consisting of biotinylated species
The method of claim 22, wherein the appendage comprises…
The method of claim 25, wherein the ORE-1001 and appendage thereto comprises the molecule having the structure…
In each case, it is unclear how the claim further limits the structure of the ORE-1001, and thus it is unclear how any of the claims further limit the method of claim 1 (see the above 112(b) rejections for claims 22-26). Thus, each of claims 22-26 are prima facie obvious for the same reasons as claim 1.
Claim 28 is directed towards “the method of claim 1, wherein the appendage obstructs the virus’ interaction with two moderately flexible helices on the side of ACE2…” As it is unclear how claim 28 further limits the method of claim 1 (see the above 112(b) rejection for claim 21), claim 28 is prima facie obvious for the same reasons as claim 1.
Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over Towler (Towler et al., ACE2 X-Ray Structures Reveal a Large Hinge-bending Motion Important for Inhibitor Binding and Catalysis*, Journal of Biological Chemistry, Volume 279, Issue 17, 2004, Pages 17996-18007) in view of Zhou (Zhou et al., A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270–273 (2020)).
Claim 27 is directed towards a method of treating or preventing an infectious disease caused by COVID-19 via administration of (S,S)-2-[1-carboxy-2-[3-(3,5-dichlorobenzyl)-3H-imidazol-4-yl]-ethylaminol-4-methylpentanoic acid (MLN-4760) wherein the compound comprises a conjugate that is positioned to block the virus from binding to ACE2. For the teachings of Towler and Zhou as they are relevant to the treatment of COVID-19 with MLN-4760, see the above 103 rejection for claim 4. Regarding the phrase, “wherein the (S,S)-2-[1-carboxy-2-[3-(3,5-dichlorobenzyl)-3H-imidazol-4-yl]-ethylaminol-4-methylpentanoic acid, or a pharmaceutically acceptable salt thereof comprises a conjugate that is positioned to block the virus from binding to ACE2,” it is unclear how the phrase further limits the method of claim 27 (see the above 112(b) rejection for claim 27). Claim 27 is therefore prima facie obvious.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/A.J.S./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
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