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
The instant application, filed 11/18/2024, is a national stage entry of PCT/GB2023/051335, filed 05/19/2023, which claims priority to GB Patent Application No. GB2207348.0, filed on 05/19/2022. Receipt is acknowledged of certified copies of papers required by 37 CFR § 1.55.
Status of Claims
Claims 1-16 were originally presented on 11/18/2024. The preliminary amendments to the claims also received on 11/18/2024 are acknowledged and entered. Claims 3-11, 13, and 14-16 were amended, claim 12 was canceled, and claims 17-24 were added.
Accordingly, claims 1-11 and 13-24 are pending.
Information Disclosure Statement
The Information Disclosure Statements received on 11/18/2024 and 01/28/2026 are acknowledged and found to be in compliance with the provisions of 37 CFR § 1.97. Accordingly, the Information Disclosure Statements have been considered.
Assessment of the Effective Filing Date of the Claims
The instant claims are drawn to a compound of formula (I), see claim 1, and its medicinal use, see claims 13-16. The instant claim 1 is shown below on the left. The priority application, GB2207348.0, filed on 05/19/2022, does not disclose the full scope of the compounds of formula (I) presently claimed. See, e.g., GB2207348.0 at 35, claim 1, also shown below. GB2207348.0 does not disclose the A variable options. Further, the R3 – R8 variables presently claimed reside in different locations about the chemical scaffold and have broader scope. See comparison below:
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Instant claim 1.
Claim 1 of GB2207348.0.
Further, GB2207348.0 discloses only 9 species of the invention. See, e.g., GB2207348.0 at 36, claim 11:
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GB2207348.0 at 36, claim 11.
Moreover, entire treatment axes currently claimed were not disclosed in GB2207348.0. See, e.g., claims 14-16 of GB2207348.0. Nowhere in GB2207348.0 does it state that the instant compounds are effective for protecting a transplant organ from ischemia and inflammation (instant claims 14-16).
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All claims encompass subject matter that was not disclosed in the priority application. Therefore, the effective filing date of the claims is the filing date of the PCT, 05/19/2023.
Specification Objections
The disclosure is objected to because of the following informalities:
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. 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.
See Specification at 1 and 107 for the hyperlinks.
The specification is objected to because of the reference to “WO 2021/115299 (Zuo)”, see Specification at 105, which appears to contain a typographical error. International Publication No. WO 2021/115299 is indeed a patent application from an inventor Zuo, but it discloses “An image collecting device (4) for collecting 3D information and a method of selecting the same”. See WO 2021/115299 at Abstract. It does not “disclose[] compounds that protect against acute kidney injury caused by many different causes.” Specification at 105.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 13, 15, and 16 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 13, it recites vague indications for the active compounds of formula (I). See “diseases caused by cellular necrosis and inflammation”. There is no standard diagnostic code for “diseases caused by cellular necrosis and inflammation”. Even if one were to read the Linkermann article the Specification at 1 cites in discussing necroinflammation,1 one would learn that whatever diseases arise from it, “[the] list is certainly incomplete”. Linkermann at 1. Accordingly, one of skill in the art would be unable to ascertain the metes and bounds of the claim.
Further see “diseases wherein the subject has experienced or is suffering from physical trauma or crush injury”. There is insufficient antecedent basis for the claim term “the subject” in this phrase. Further, it is unclear which diseases fall into this category. There is no standard diagnostic code for “diseases wherein the subject has experienced or is suffering from physical trauma or crush injury”. The same applies to “diseases wherein the subject has experienced or is suffering from … exposure to electrical current, extreme physical exertion or activity, and temperature extremes associated with or at risk for onset of rhabdomyolysis”.
Moreover, see “diseases wherein the subject has a pre-existing condition or disease that increases the subject's risk of developing a kidney condition or disease when exposed to a nephrotoxin”. Further, see “diseases where a pre-existing condition or disease increases the risk of chronic kidney disease optionally wherein there is a history of renal impairment or a requirement for dialysis”. Last, see “diseases associated with reduced blood flow”.
There are no standard diagnostic codes or fixed lists of “diseases” that arise from any of these clinical findings. As a result, one of skill in the art would be unable to ascertain the metes and bounds of the claim. Therefore, claim 13 is rejected as indefinite.
Regarding claim 15, it recites the limitation "the organ" in the wherein clause. There is insufficient antecedent basis for this limitation in the claim. The lack of antecedent basis for “the organ” makes it unclear if “the organ” is removed from the “organ donor” recited in the claim, or if “the organ” is just some other organ removed from some other source.
Accordingly, claim 15 is rejected as indefinite.
Regarding claim 16 the phrases "preferably” and “more preferably” renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. Preferences are properly set forth in the Specification. See MPEP § 2173.05(d). Further, there is insufficient antecedent basis for the claim term “the transplant organs”.
Accordingly, claim 16 is rejected as indefinite.
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.
Claims 1-11 and 13-24 Obvious over US’092 in view of Patani 1996, Selcia 2018, Mackman 2018, Kerr 2018, Hellinger 2012, WO’601, and US’441
Claim(s) 1-11 and 13-24 is/are rejected under 35 U.S.C. 103 as being unpatentable over US’0922 in view of Patani 1996,3 Selcia 2018,4 Mackman 2018,5 Kerr 2018,6 Hellinger 2012,7 WO’601,8 and US’441.9
The instant claims are drawn to compounds of formula (I) and their medicinal use as cyclophilin inhibitors. The instant compound designated compound 18 is an embodiment of claims 1-3, 5-6, 8, 10-11, 13-17, 20-21, and 24.
US’092 teaches the cyclophilin inhibitor it designates as compound 48 at col. 253. See also, US’092 at col. 501, claim 21, specifically reciting compound 48. The instant compound 18 and compound 48 of US’092 are classical bioisosteres, with the only difference in the chemical structure being the exchange of a nitrogen for a CH group.
See below structures of the instant formula (I), compound 18, and US’092 compound 48:
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Instant formula (I)
Instant compound 18
US’092 compound 48
Further, the instant compound designated compound 2 is an embodiment of claims 1-4, 6, 8, 10-11, and 13-24. US’092 teaches the cyclophilin inhibitor compound it designates as compound 18 at col. 132. See structures below, left and right, respectively. These compounds are also classical bioisosteres, with the same exchange of a nitrogen for a CH group.
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Instant compound 2
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US’092 compound 18
The compounds of US’092 belong to a family of compounds represented by the general structure depicted in US’092 at cols. 2 and 468, claim 1. The structure from col. 2 is shown below:
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US’092 General Structure
Each variable has near complete overlap with the instant claims, except for the A2 variable of US’092 reciting “
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”, and not its bioisosteric equivalent, “N(R8)-heteroarylene”. Further, US’092 does not appear to expressly teach bridging the instant R7-R8 variables with an alkyl group to constrain the conformation, as recited in the instant claims (see, e.g., instant claim 7).
Moreover, the biological properties of the compounds of US’092 were well-known. See US’092 at cols. 1-2 (discussing that the compounds were sanglifehrin derivatives and therefore may be used for similar purposes). See also, US’092 at cols. 464-468, where it specifically teaches that the compounds inhibit cyclophilin binding and suppress viral replication. Due to their PPIase activity, US’092 at cols 68-69 teaches that the compounds were effective for treating Flaviviridae and Coronaviridae infections, diseases caused directly or indirectly from such infections, cancer, and inflammation.
Yet, US’092 does not appear to explicitly teach the instantly claimed bioisosteres.
However, one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in making the bioisosteric exchange of the CH of US’092 with a nitrogen because,
Patani 1996 teaches that by definition, there was a reasonable expectation that the bioisosteric compound would affect the same biological targets and thereby have related properties,
Selcia 2018 teaches that there was a reasonable expectation that the bioisosteres would be effective as potent inhibitors of not only cyclophilin A, but also cyclophilin D,
Mackman 2018, Hellinger 2012, and Kerr 2018 teach that there was a reasonable expectation that certain bioisosteres would show the ability to cross the blood brain barrier, and related indications for APIs in this class,
WO’601 teaches that there was a reasonable expectation that the bioisosteres would have efficacy in organ-transplantation procedures, and
US’441 teaches that there was a reasonable expectation that the rigidified and conformationally constrained variants of the bioisosteres would have efficacy as cyclophilin inhibitors.
Patani 1996
The exchange of N for CH results in compounds that are bioisosteres. By definition, bioisosteres affect the same pharmacological target as agonists or antagonists and, thereby, have biological properties which are related to each other.
Patani 1996 has been cited thousands of times by numerous authors for its review of “Bioisosterism: A Rational Approach in Drug Design”. See Patani 1996 at Title. On the first page, it explains that “Bioisosterism represents one approach used by the medicinal chemist for the rational modification of lead compounds into safer and more clinically effective agents.” Patani 1996 at 3147. The approach was considered “intuitive”, id., and had its roots back to 1919, id. at 3148. Bioisosteres are “Compounds or groups that possess near-equal molecular shapes and volumes, approximately the same distribution of electrons, and which exhibit similar physical properties...”. Id. “The critical component for bioisosterism is that bioisosteres affect the same pharmacological target as agonists or antagonists and, thereby, have biological properties which are related to each other.” Id.
“Bioisosteres have been classified as either classical or nonclassical.” Id. One such group of classical bioisosteres were those “according to Grimm”, see Patani 1996 at 3148, Table 2 and surrounding text (second column shows the N and CH exchange):
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Patani 1996 at 3148, Table 2.
Accordingly, the exchange of N for CH results in bioisosteres, that by definition, affect the same pharmacological target as agonists or antagonists and, thereby, have biological properties which are related to each other.
Selcia 2018
From the outset, Selcia 2018 reports on the publication of a “paper entitled ‘Discovery of a Potent and Orally Bioavailable Cyclophilin Inhibitor Derived from the Sanglifehrin Macrocycle’ by authors from Selcia.” The paper cited in Selcia 2018 is Mackman 2018, which is discussed later in this rejection. Mackman 2018 details the development of the compounds of US’092.
Selcia 2018 identified the compounds of US’092 as lead compounds for further development. See Selcia 2018 at 1 (“The authors describe the identification of synthetic, macrocyclic, orally bioavailable cyclophilin inhibitors with potent HCV activity. These compounds also provide starting points for drug discovery programmes in several other major diseases where there is a high level of existing unmet need.”)
In Selcia 2018 at 2, the article explicitly states that the compounds disclosed in US’092 were “potent inhibitors of cyclophilin D and protect against opening of the mitochondrial permeability transition pore”:
The compounds described in the The Journal of Medicinal Chemistry paper are examples of a new class of fully synthetic cyclophilin inhibitors that Cypralis has designated as ‘cyprolides’. They are highly potent, non-immunosuppressive, low molecular weight cyclophilin inhibitors with excellent drug properties. These compounds are potent inhibitors of cyclophilin D and protect against opening of the mitochondrial permeability transition pore. This property leads to protection of cells and tissues associated with several diseases such as neurodegeneration, fibrosis and other mitochondrially-mediated diseases.
Selcia 2018 at 2 (emphasis added).
Vicky Steadman Ph.D., explains in Selcia 2018 at 2, that the cyclophilin inhibitors disclosed in US’092 were developed “ ‘in partnership with Gilead’s anti-viral research group’ ”. This statement was consistent with US’092 disclosing primarily anti-viral treatment indications for its compounds.
However, “In January 2018, Gilead exclusively licensed to Cypralis the development and commercialization rights to certain cyclophilin inhibitors arising from the Gilead/Selcia collaboration, in all fields except for oncology and virology.” Selcia 2018 at 1.
Mike Peel Ph.D., of Cypralis, is quoted in the article as stating that “Cypralis is developing its first-in-class, non-immunosuppressive cyclophilin inhibitors as new therapies for degenerative diseases including Parkinson’s disease and fibrosis.” Selcia 2018 at 1-2.
The quotation from Dr. Peel strongly suggests that the compounds of US’092 were brain penetrant, in view of the Parkinson’s disease indication sought.
Mackman 2018 and Hellinger 2012
Mackman 2018 discloses the development of the known US’092 compounds 48 and 18. See, e.g., Mackman 2018 at 9480, compounds 3 and 34, which are the US’092 compounds 48 and 18, respectively.10
The inventors of US’092 utilized intuitive, classical bioisosteric exchanges throughout the development of these compounds. See, e.g., Mackman 2018 at 9477, compounds 18 and 19, which are classical bioisosteres. While replacing the CH of 18 with a nitrogen atom slightly decreases the lipophilicity (see log D), and slightly increases potency, both compounds affect the same biological target and have related biological properties.
Even compounds 19 and 20 of Mackman 2018 at 9477 were considered bioisosteres. See, e.g., Patani 1996 at 3152-3154 (discussing that methyl and hydrogen were known bioisosteric replacements). In the case of compounds 19 and 20, the exchange of H for methyl restored the lipophilicity offset from the introduction of the nitrogen. Moreover, see compounds 20 and 34, which were considered classical bioisosteres. The marked increase in lipophilicity demonstrated by this classical bioisosteric NH-O exchange was “not unexpected”. See Mackman 2018 at 9479, right column, discussing the formation of an internal hydrogen bond, and its impact on the beneficial “apical to basolateral permeability” that resulted from this bioisosteric exchange.
Mackman 2018 discloses key PK/PD parameters of the compounds built from its scaffold. It shows how to tune lipophilicity by making minor modifications to the chemical scaffold, and how to tune permeability, as shown in the Caco-2 AB/BA values disclosed throughout.
In particular, the Caco-2 AB/BA parameters reported for various compounds in Mackman 2018 indicated that some of the compounds were possibly brain penetrant. See Hellinger 2012, which discloses the known approximation of blood-brain barrier (“BBB”) penetration based upon Caco-2 AB/BA measurements. See, e.g., Hellinger 2012 at 349 (“In our study, the rate of penetration (Papp) of 10 reference drugs with both a passive and efflux mechanism has been determined in the rat brain endothelial model of BBB and in Caco-2, VB-Caco-2, and MDCK-MDR1. Plotting the in vivo permeability data of all 10 drugs tested against the in vitro Papp data resulted in a linear correlation when a tissue binding correction was applied for them.”).
While the correlation between BBB penetration and PappA-B was not perfectly linear, this model for native Caco-2 penetration was known to still yield predictive power.
Returning to the Caco-2 data reported in Mackman 2018, its compound 34, which is compound 18 of US’092, indicated possible brain penetration. See, e.g., Mackman 2018 at Table 4, reporting
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for compound 34, efflux ratio of ~2.8. Combined with the drugs elevated lipophilicity, an ordinary chemist at the time of filing would reasonably expect that the compound penetrated the BBB to a certain extent.
Kerr 2018
Kerr 2018 is a YouTube video from a presentation dated 5th Feb 2018 by the CEO of Cypralis regarding the cyclophilin inhibitors in their portfolio. The presentation was dated 5th Feb 2018, one month after “Gilead exclusively licensed to Cypralis the development and commercialization rights to certain cyclophilin inhibitors arising from the Gilead/Selcia collaboration”. Selcia 2018 at 1. Their portfolio includes many of the compounds disclosed in US’092.11
Around the 2:40 mark, the presentation provides common indications for inhibitors of cyclophilin A, B, and D. As the Selcia 2018 article explained, the compounds discussed in Mackman 2018 and thereby US’092 are “potent inhibitors of cyclophilin D”. From US’092, these compounds were also potent inhibitors of cyclophilin A. Therefore, according to Kerr 2018, the compounds of US’092 were indicated at least for kidney injury, pancreatitis, Parkinson’s disease, Alzheimer’s disease, and ALS/Lou Gehrig’s disease. See below screenshot of the presentation:
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Second, the presentation around the 7:30 mark discusses the cyclophilin inhibitor API designated CC-4066. CC-4066 was indicated for acute kidney and pancreas injury, and was under development with Farsight Shanghai:
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Third, the presentation around the 9:20 mark discusses that the APIs within Cypralis’ portfolio were brain penetrant. Therefore, brain penetrant cyclophilin inhibitors were known in the art at the time of filing:
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Whether or not Mr. Kerr was discussing the compounds of US’092 specifically when stating that the company was in possession of brain penetrant cyclophilin inhibitors is unclear. Nevertheless, the presentation connects “brain penetrant cyclophilin inhibitors” to the “Parkinson’s disease, Alzheimer’s and other neurodegenerative conditions” indications.
WO’601
WO’601, filed by Farsight Shanghai, teaches common indications for dual cyclophilin A and D inhibitors. See, e.g., WO’601 at 20 around lines 10-20 (stating that the disclosed compounds were dual cyclophilin A and D inhibitors), and at 21-27, which teach many of the instantly claimed indications. See, e.g., the indications for treatment of ischemia-reperfusion injury (“IRI”) at page 23, “for preserving an organ and/or protecting an organ from organ injury, such as during transplantation surgery” at page 24, for use in a living organ donor at page 25, and for treating kidney conditions associated with nephrotoxins at page 27. Accordingly, a known use of dual cyclophilin A and D inhibitors included their administration for organ perseveration and transplantation purposes.
US’441
As indicated in Mackman 2018 and discussed in the footnote above for citations (31)-(33) of the article, the development of the compounds of US’092 were first chronicled in the patent literature. Citation (32) of Mackman 2018 is to WO 2013185103A1. US’441 is the US Patent that is in family with the WO 2013185103A1 international application. During the development of the compounds of US’092, the inventors utilized common techniques to restrain the macrocycle conformations, such as bridging the positions corresponding to the instant R7-R8 .
See, e.g., US’441 at col. 690, claim 1, teaching a similar scaffold the compounds of US’092. See, e.g., compounds 150 and 151, US’441 at col 618, which are rigidified, classical bioisosteric versions of the US’092 compound 18, and are classical bioisosteres of the instant compound designated 8, shown below.:
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Compounds 150 and 151 of US’441
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US’092 compound 18
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Instant compound 8
Compound 150 was more active than compound 151. See US’441 at col. 689.
The instant compounds 18 and 2 were obvious at the time of filing
As explained, the instant compound designated compound 18 is an embodiment of claims 1-3, 5-6, 8, 10-11, 13-17, 20-21, and 24. It is a classical bioisostere of US’092 compound 48. US’092 compound 48 is compound 3 of Mackman 2018. The only difference between the chemical structures of the bioisosteres is the exchange of a single CH for N.
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Instant compound 18
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US’092 compound 48, or compound 3 of Mackman 2018
Further, the instant compound designated compound 2 is an embodiment of claims 1-4, 6, 8, 10-11, and 13-24. It is a classical bioisostere of US’092 compound 18. US’092 compound 18 is compound 34 of Mackman 2018. The only difference between the chemical structures of the bioisosteres is the exchange of a single CH for N.
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Instant compound 2
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US’092 compound 18, or compound 34 of Mackman 2018
For each set of bioisosteres, there was by definition a reasonable expectation that they would affect the same pharmacological targets, and, thereby, have biological properties which are related to each other. In view of the well-known properties of these compounds as dual cyclophilin A and D inhibitors, there was a reasonable expectation that the bioisosteres, when administered to a patient in the form a pharmaceutical composition,12 would have a therapeutic benefit for not only treating viral infections as discussed in US’092, but also in protecting patients from nephrotoxins, as well as protecting and persevering organs for use in transplantations. Further, there was a reasonable expectation that some of the compounds within the family of compounds taught in US’092 inherently had the ability to penetrate the blood-brain barrier, such as the US’092 compound 18 (compound 34 of Mackman 2018). It was therefore reasonable to expect that bioisosteres of some of the compounds of US’092, such as a bioisostere of its compound 18, would also cross the blood-brain barrier.
It would take only ordinary and routine experimentation by following simple preclinical procedures of testing the bioisosteres in animal models of disease to determine effective amounts of the compounds to administer to patients and organs. Such preclinical procedures were well within the skills of an ordinary chemist at the time of filing, as evidenced at least by the preclinical studies exemplified in Mackman 2018.
Accordingly, one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in preparing the instant claimed bioisosteres of the US’092 compounds 18 and 48 and using them in the methods presently claimed. Therefore, claims 1-6, 8, 10-11, and 13-24 were obvious at the time of filing.13
The instant compound 8 was obvious at the time of filing
Regarding claim 7, the instant compound 8 is an embodiment of this claim. The instant compound 8 is a conformationally constrained and rigidified bioisostere of US’092 compound 18, i.e., compound 34 of Mackman 2018. Moreover, it is an exact classical bioisostere of compound 150 of US’441, discussed several pages back. The only structural difference between compound 150 of US’441 and the instant compound 8 is the classical bioisosteric exchange of CH for N, and NH for O (see Patani 1996 at 3148, Table 2, which shows the NH for O bioisosteric exchange).
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Therefore, one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in preparing the instant compound 8, because there was a reasonable expectation the instant compound 8 would be effective as a cyclophilin inhibitor, given that it was a classical bioisostere of the known API, compound 150 of US’441.
Accordingly, claim 7 was obvious at the time of filing.
The instant compound 76 was obvious at the time of filing
Regarding claim 9, it is drawn derivatization of the instant R6 variable. The instant compound 76 is an embodiment of this claim. The instant compound 76 is a classical bioisostere of US’441 compound 120, shown below. The only structural difference between the two compounds is the classical bioisosteric exchange of CH for N, and NH for O:
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Instant compound 76
US’441 compound 120 was disclosed at col. 525. It showed stellar activity in assays, see US’441 at col. 689. Therefore, one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in preparing the instant compound 76, because there was a reasonable expectation the instant compound 76 would be effective as a cyclophilin inhibitor, given that it was a classical bioisostere of the known API, US’441 compound 120.
Accordingly, claim 9 was obvious at the time of filing.14
Claims 1-11 and 13-24 Obvious over US’092 in view of Patani 1996, Selcia 2018, Mackman 2018, Kerr 2018, Hellinger 2012, WO’601, US’441, and Meertens 2023
Claim(s) 1-11 and 13-24 is/are rejected under 35 U.S.C. 103 as being unpatentable over US’092 in view of Patani 1996, Selcia 2018, Mackman 2018, Kerr 2018, Hellinger 2012, WO’601, US’441, and Meertens 2023.15
The preceding rejections of claims 1-11 and 13-24 under 35 U.S.C. 103 as being unpatentable over US’092 in view of Patani 1996, Selcia 2018, Mackman 2018, Kerr 2018, Hellinger 2012, WO’601, and US’441, are incorporated herein and restated in full after the following discussion of Meertens 2023.
As discussed in Kerr 2018, the cyclophilin inhibitor API designated CC-4066 was indicated for acute kidney and pancreas injury, and was under development with Farsight Shanghai:
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Meertens 2023 explains that the API designated CC-4066 was a potent dual inhibitor of Meertens 2023 of Cyclophilin A and D, and that it was also useful for organ transplantation. See, e.g., Meertens 2023 at 2, which teaches that “CC-4066 (Cypralis, United Kingdom) is a potent dual inhibitor of Cyclophilin A and D proteins which may be beneficial in a broad range of diseases including IRI in kidney transplantation. Cyclophilin D inhibition prevents hypoxia-induced cell damage, while Cyclophilin A inhibition minimizes reperfusion injury (19–25).”
Meertens 2023 teaches a method of protecting a transplant organ from ischemia and inflammation comprising administering a dual cyclophilin A and D inhibitor, wherein the transplant organ is perfused and stored in a solution containing 15 µM CC-4066. See entire article, and in particular page 3, teaching “15 μM CC-4066”. The supporting information is also attached.
Accordingly, Meertens 2023 supports a finding of a reasonable expectation of success in using the classical bioisosteres of the compounds of US’092 for transplantation procedures. While the chemical structure of CC-4066 does not appear to be known, Meertens 2023 teaches a procedure one of ordinary skill in the art at the time of filing could follow to determine effective amounts of the classical bioisosteres of the compounds of US’092 for use in transplantation procedures. Further, being a dual cyclophilin A and D inhibitor, it represented an API from the same class as the claimed classical bioisosteres. It would require only ordinary and routine experimentation following the procedure set forth in Meertens 2023 to arrive at the optimal concentrations required to protect the transplant organ for these procedures.
Now, the preceding discussion of Meertens 2023 is incorporated into the prior rejections of the claims under 35 U.S.C. 103 as being unpatentable over US’092 in view of Patani 1996, Selcia 2018, Mackman 2018, Kerr 2018, Hellinger 2012, WO’601, and US’441, which are restated in full.
Therefore, claim(s) 1-11 and 13-24 are rejected as obvious over US’092 in view of Patani 1996, Selcia 2018, Mackman 2018, Kerr 2018, Hellinger 2012, WO’601, US’441, and Meertens 2023.
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.
NSDP to US’092 in view of Patani 1996
Claims 1-6, 8, 10-11, and 17-24 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 17, 21 and 27 of U.S. Patent No. US 9062092 B2, i.e., “US’092”, in view of Patani 1996. The instant application and the US’092 patent share inventors.
The instant compound designated compound 18 is an embodiment of compound claims 1-3, 5-6, 8, 10-11, 17, 20-21, and 24.
US’092 at col. 501, claim 21, teaches the cyclophilin inhibitor it designates as compound 48. See also¸ US’092 at col. 253. The instant compound 18 and compound 48 of US’092 are classical bioisosteres, with the only difference in the chemical structure being the exchange of a nitrogen for a CH group.
See structures of the instant formula (I), compound 18, and US’092 compound 48:
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Instant formula (I)
Instant compound 18
US’092 compound 48
Further, the instant compound designated compound 2 is an embodiment of compound claims 1-4, 6, 8, 10-11, and 17-24. US’092 teaches the cyclophilin inhibitor compound it designates as compound 18 at claim 17, col. 479. See also, US’092 at col. 132. These compounds are also classical bioisosteres, with the same exchange of a nitrogen for a CH group.
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Instant compound 2
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US’092 compound 18
The compounds of US’092 belong to a family of compounds represented by the general structure depicted in US’092 at col. 468, claim 1, shown below:
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US’092 General Structure
Each variable has near complete overlap with the instant claims, except for the A2 variable of US’092 reciting “
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”, and not its bioisosteric equivalent, “N(R8)-heteroarylene”. US’092 at col. 510, claim 27 teaches pharmaceutical compositions of its compounds.
Claim interpretation is required to determine the utility of the compounds of US’092. See MPEP 804 II.B.1.
The biological properties of the compounds of US’092 were well-known. See US’092 at cols. 1-2 (discussing that the compounds were sanglifehrin derivatives and therefore may be used for similar purposes). See also, US’092 at cols. 464-468, where it specifically teaches that the compounds inhibit cyclophilin binding and suppress viral replication. Due to their PPIase activity, US’092 at cols 68-69 teaches that the compounds were effective for treating Flaviviridae and Coronaviridae infections, diseases caused directly or indirectly from such infections, cancer, and inflammation.
While the US’092 claims do not appear to explicitly teach the instantly claimed bioisosteres, one of ordinary skill in the art at the time of filing the application that led to the US’096 patent, and in possession of its subject matter, would have a reasonable expectation of success in making the bioisosteric exchange of the CH of US’092 with a nitrogen because, by definition, there was a reasonable expectation that the bioisosteric compound would affect the same biological targets and thereby have related properties, see Patani 1996, discussed below.
Patani 1996 reviews the well-known method of modifying a known active compound to tweak its activity (e.g. potency, bioavailability, solubility, and so on) while maintaining the same target biological activity, which is known as bioisosterism. See, e.g., Patani 1996, at 3147-3149, discussing the history of this well-known method used in drug design. As Patani 1996 at 3147 states, the methodology of bioisosteric replacement was “intuitive” and utilized by “medicinal chemist[s] for the rational modification of lead compounds into safer and more clinically effective agents.” See also, Patani 1996 at 3148, which states “The critical component for bioisosterism is that bioisosteres affect the same pharmacological target as agonists or antagonists and, thereby, have biological properties which are related to each other.”
N and CH exchanges were known to result in compounds classified as classical bioisosteres “according to Grimm”. See Patani 1996 at 3148, Table 2, which is excerpted below.
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Patani 1996 at 3148, Table 2.
Accordingly, one of ordinary skill in the art the time of filing the application that led to the US’096 patent, and in possession of its subject matter, would have a reasonable expectation of success in preparing the classical bioisosteres of the known US’092 compounds 48 and 18, because there was a reasonable expectation that the classical bioisosteres would “affect the same pharmacological target as agonists or antagonists and, thereby, have biological properties which are related to each other.” Patani 1996 at 3148. Therefore, the bioisosteric exchange from the CH of US’096 to the nitrogen in the instant claims was “intuitive” and obvious at the time of filing.
As a result, claims 1-6, 8, 10-11, and 17-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 17, 21 and 27 of U.S. Patent No. US 9062092 B2.
NSDP to US’392 in view of Patani 1996
Claims 1-3, 5-6, 8, 10-11, 17, 20-21, and 24 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, and 9-11 of U.S. Patent No. US 10472392 B2,16 i.e., “US’392”, in view of Patani 1996. The instant application and the US’392 patent share inventors and assignees.
The instant compound designated compound 18 is an embodiment of compound claims 1-3, 5-6, 8, 10-11, 17, 20-21, and 24.
US’392 at col. 455, claim 9, teaches the cyclophilin inhibitor it designates as compound 48. See also¸ US’392 at col. 248. Claims 10-11 of US’392 teach its pharmaceutical compositions. The instant compound 18 and compound 48 of US’392 are classical bioisosteres, with the only difference in the chemical structure being the exchange of a nitrogen for a CH group.
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US’392 compound 48
Claim interpretation is required to determine the utility of the compounds of US’392. See MPEP 804 II.B.1.
The biological properties of the compounds of US’392 were well-known. See US’392 at cols. 1-2 (discussing that the compounds were sanglifehrin derivatives and therefore may be used for similar purposes). See also, US’392 at cols. 448-452, where it specifically teaches that the compounds inhibit cyclophilin binding and suppress viral replication. Due to their PPIase activity, US’392 at cols 66-67 teaches that the compounds were effective for treating Flaviviridae and Coronaviridae infections, diseases caused directly or indirectly from such infections, cancer, and inflammation.
While the US’392 claims do not appear to explicitly teach the instantly claimed bioisosteres, one of ordinary skill in the art at the time of filing the application that led to the US’392 patent, and in possession of its subject matter, would have a reasonable expectation of success in making the bioisosteric exchange of the CH of US’392 with a nitrogen because, by definition, there was a reasonable expectation that the bioisosteric compound would affect the same biological targets and thereby have related properties, see Patani 1996, discussed below.
Patani 1996 reviews the well-known method of modifying a known active compound to tweak its activity (e.g. potency, bioavailability, solubility, and so on) while maintaining the same target biological activity, which is known as bioisosterism. See, e.g., Patani 1996, at 3147-3149, discussing the history of this well-known method used in drug design. As Patani 1996 at 3147 states, the methodology of bioisosteric replacement was “intuitive” and utilized by “medicinal chemist[s] for the rational modification of lead compounds into safer and more clinically effective agents.” See also, Patani 1996 at 3148, which states “The critical component for bioisosterism is that bioisosteres affect the same pharmacological target as agonists or antagonists and, thereby, have biological properties which are related to each other.”
N and CH exchanges were known to result in compounds classified as classical bioisosteres “according to Grimm”. See Patani 1996 at 3148, Table 2, which is excerpted below.
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Patani 1996 at 3148, Table 2.
Accordingly, one of ordinary skill in the art the time of filing the application that led to the US’392 patent, and in possession of its subject matter, would have a reasonable expectation of success in preparing the classical bioisostere of the known US’392 compounds 48, because there was a reasonable expectation that the classical bioisostere would “affect the same pharmacological target as agonists or antagonists and, thereby, have biological properties which are related to each other.” Patani 1996 at 3148. Therefore, the bioisosteric exchange from the CH of US’392 to the nitrogen in the instant claims was “intuitive” and obvious at the time of filing.
As a result, claims 1-3, 5-6, 8, 10-11, 17, 20-21, and 24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, and 9-11 of U.S. Patent No. US 10472392 B2.
Prior Art Cited but not Applied
The prior art made of record and not relied upon is considered pertinent to applicant’s disclosure.
Doak, Bradley C., and Jan Kihlberg. "Cyclophilin succumbs to a macrocyclic chameleon." Journal of Medicinal Chemistry 61.21 (2018): 9469-9472.
Further chronicles the development of US’092 compounds.
Steadman, Victoria A., et al. "Discovery of potent cyclophilin inhibitors based on the structural simplification of sanglifehrin A." Journal of medicinal chemistry 60.3 (2017): 1000-1017.
Further chronicles the development of US’092 compounds.
Paulsen, Janet L., et al. "Evaluation of free energy calculations for the prioritization of macrocycle synthesis." Journal of Chemical Information and Modeling 60.7 (2020): 3489-3498.
Further chronicles the development of US’092 compounds.
Sedrani, Richard, et al. "Sanglifehrin− Cyclophilin interaction: degradation work, synthetic macrocyclic analogues, X-ray crystal structure, and binding data." Journal of the American Chemical Society 125.13 (2003): 3849-3859.
Teaches how to make sanglifehrin derivatives.
Martin Cabrejas, Luisa M., et al. "Macrolide Analogues of the Novel Immunosuppressant Sanglifehrin: New Application of the Ring‐Closing Metathesis Reaction." Angewandte Chemie International Edition 38.16 (1999): 2443-2446.
Teaches how to make sanglifehrin derivatives. See, e.g., Cabrejas 1999 at 2444, Figure 1:
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Cabrejas 1999 at 2444, Figure 1.
Conclusion
No claims allowed.
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/C.E.R./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 Linkermann, Andreas. "Death and fire—the concept of necroinflammation." Cell Death & Differentiation 26.1 (2019): 1-3, hereinafter “Linkermann”.
2 Steadman; Victoria Alexandra, et al., “Macrocyclic Inhibitors Of Flaviviridae Viruses”, U.S. Patent No. US 9062092 B2, published 2015-06-23, hereinafter “US’092”. US’092 is in family with International Application WO 2013185093 A1, cited in the IDS received 11/18/2024 as FOR Cite 1.
3 Patani, George A., and Edmond J. LaVoie. "Bioisosterism: a rational approach in drug design." Chemical reviews 96.8 (1996): 3147-3176, hereinafter “Patani 1996”.
4 Anonymous, “Identification of synthetic, macrocyclic, orally bioavailable cyclophilin inhibitors with potent HCV activity, published in The Journal of Medicinal Chemistry”, dated 09-17-2018, available online at https://www.selcia.com/news/identification-synthetic-macrocyclic-orally-bioavailable-cyclophilin-inhibitors-potent-hcv, hereinafter “Selcia 2018”.
5 Mackman, Richard L., et al. "Discovery of a potent and orally bioavailable cyclophilin inhibitor derived from the sanglifehrin macrocycle." Journal of medicinal chemistry 61.21 (2018): 9473-9499, hereinafter “Mackman 2018”. Mackman 2018 was cited in the IDS received 11/18/2024 as NPL Cite 1.
6 “Cypralis CEO Simon Kerr Biotech and Money Presentation 2018”, posted by “Cypralis Ltd” on Feb 16, 2018, available online at https://www.youtube.com/watch?v=gZPFIEBYq5Q, hereinafter “Kerr 2018”. Screenshots from the presentation are attached hereto along with the transcript of the presentation generated by YouTube.
7 Hellinger, Éva, et al. "Comparison of brain capillary endothelial cell-based and epithelial (MDCK-MDR1, Caco-2, and VB-Caco-2) cell-based surrogate blood–brain barrier penetration models." European journal of pharmaceutics and biopharmaceutics 82.2 (2012): 340-351, hereinafter “Hellinger 2012”.
8 MAK CHING-PONG, “CYCLOPHILIN INHIBITORS AND USES THEREOF”, International Publication No. WO 2021190601 A1, published 2021-09-30, hereinafter “WO’601”. WO’601 was cited in the IDS received 11/18/2024 as FOR Cite 2.
9 Aciro; Caroline, et al., “Macrocyclic Inhibitors Of Flaviviridae Viruses”, U.S. Patent No. US 9145441 B2, published 2015-09-29, hereinafter “US’441”.
10 See also, Mackman 2018 at 9498, citation (31) to WO 2013185093A1, which was the international publication in family with US’092. Citation (32) is to WO 2013185103A1, which is in family with US’441. Citation (33) is to WO 2013185090A1, which was cited in the IDS received on 1/28/2026 as FOR cite 1.
11 See, e.g., U.S. Patent No. US 10472392 B2, which is in family with US’092, and is assigned to Cypralis Ltd.
12 See, e.g., US’092 at col. 510, claim 27, teaching standard pharmaceutical compositions, which one of ordinary skill in the art at the time of filing could adapt for the bioisosteres, particularly in view of their shared structural similarity.
13 Regarding claim 16 in particular, which is drawn to the amount of the dual cyclophilin A and D inhibitor required to sustain the transplant organ, it would only take ordinary and routine experimentation to determine such an amount, particularly in view of WO’601 teaching that these compounds were effective for this purpose. Further, the specification fails to provide any evidence as to any criticality regarding the effective amount used in this method. Indeed, it never even discusses perfusing and storing a transplant organ using a solution containing a 0.01-100, preferably 0.01-50, more preferably 0.01-10 micromolar concentration of any compound. Therefore, the claim, which was already rejected as indefinite, seems to simply recite obvious and arbitrary limitations.
14 The examiner notes that derivatization of the instant R6 has been well explored these compounds. See, e.g., Mackman 2018 at 9474, Figure 1, which shows the chemical structure of sanglifehrin A, bearing a meta-tyrosine. The inventors of sanglifehrin A derivatives discovered that this side chain could be modified to incorporate a variety of different substituents, for example, by changing the amino acid to phenylalanine. See, e.g., US’092 and US’441 R4 variables. The swap to phenylalanine retained efficacy in cyclophilin assays, e.g., compound 120 of US’441.
15 Meertens, Pommelien, et al. "CC-4066 therapy delivered to kidneys during cold storage and assessed with normothermic reperfusion is feasible and safe." Frontiers in Transplantation, vol. 2 (May 11, 2023): 1166661, hereinafter “Meertens 2023”. The supporting information for Meertens 2023 is attached hereto
16 Aciro; Caroline, et al., “Macrocyclic Inhibitors Of Flaviviridae Viruses”, U.S. Patent No. US 10472392 B2, published 2019-11-12, hereinafter “US’392”.
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