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 08/01/2024, is the national stage entry of PCT/US2023/012230, filed 02/02/2023, which claims priority to U.S. Provisional Patent Application No. 63/306,344, filed on 02/03/2022.
Information Disclosure Statement
The Information Disclosure Statement received on 01/08/2025 is acknowledged and found to be in compliance with the provisions of 37 CFR § 1.97. Accordingly, the Information Disclosure Statement has been considered.
Status of Claims
Claims 1-43 were originally presented on 08/01/2024. The preliminary amendments to the claims, received on 05/23/2025, are acknowledged and entered. Claims 5-9, 11-26, and 42-43 were canceled, and claims 3, 4, 29-33, 36, 37, and 38-41 were amended.
Accordingly, claims 1-4, 10, and 27-41 are pending.
Assessment of the Effective Filing Date of the Claims
The claims are afforded the filing date of the PCT, which is 02/02/2023. The PCT is where support for the instantly claimed therapeutic dosing regimen first appears, as discussed below.
The claims are drawn to the medicinal use of active designated Compound I, which is shown below, or its pharmaceutically acceptable salts, or its undisclosed deuterated derivatives.
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In particular, the claims require a specific dosing regimen of administering to a cystic fibrosis patient in need 0.1 mg to 50 mg of the active. Applicant reports that the active is a CFTR-modulating compound. Accordingly, the active is potentially useful for treating certain aspects of cystic fibrosis. Applicant discloses in the specification at 131-135 that it completed portions of first-in-human trials in healthy participants studying administration of the above active. No efficacy data were disclosed. No pharmacokinetics were presented. No patients were treated.
As of the filing of the provisional priority application, certain phases of the first-in-human studies were not started or were incomplete (e.g., part A and B dose determination, and part C studying drug-drug interactions). As a result, the provisional lacks written description support for certain discoveries learned from the ongoing studies. See, e.g., Figures 1-3 of the provisional application.
Further, see claim 1 of the provisional, at 69, shown below, which provides written description support for a therapeutic dosing regimen for treating cystic fibrosis wherein the dosing is from 5 mg to 100 mg of the active:
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Claim 1 of the provisional, at 69.
The claims are not drawn to the treatment regimen disclosed in the provisional. Instead, the claims are drawn to a brand-new treatment regimen wherein the doses administered are much lower than what the provisional supports. Something clearly happened between filing the provisional and the PCT that caused Applicant to completely revise the claimed invention.
Indeed, nowhere in the provisional does it state administer 0.1 mg to 50 mg of the active to cystic fibrosis patients in need. There is no written description support in the provisional for the 0.1 mg dose recited in claim 1. Applicant added this dosing regimen in the filing of the PCT. The same is true with the 0.25 mg dose, claims 2-3. Further, the provisional does not provide the 1 mg dose, claim 4. Moreover, the 1.5 mg dose was not provided in the provisional, claim 31. The specific 4 and 8 mg doses recited in claims 32 and 33 were not provided in the provisional. It appears that not a single specifically claimed dosing regimen has support from the provisional.
Moreover, every pending claim recites or depends upon a claim that recites specific dosing that was not provided in the provisional.
This downward revision in the treatment regimen was significant. Utilizing a typical log2 dose doubling scale, the downward revision from 5 mg to 0.1 mg represents 5-6 steps down from the initially planned dose. Whatever happened between the filing of the provisional and the PCT that required the investigators of the clinical trial to completely revise the treatment regimen is not addressed at all in the Specification. Perhaps the drug was toxic and required downward revisions, or perhaps a different polymorphic form of the API, or some salt or deuterated derivative thereof was instead administered that had entirely different PK. Whatever the case may be, nothing in the provisional provides support for the currently claimed treatment regimen.
Last, while FIG. 1 of the provisional provides the doses of 0.6 mg and 2 mg, these doses were not disclosed in the context for treating cystic fibrosis. Instead, they were just doses given to healthy participants. Therefore, the doses of 0.6 mg and 2 mg given to healthy participants that were disclosed in the provisional do not provide written description support for the instant claims.
Accordingly, the claims are afforded the filing date of the PCT, which is 02/02/2023. The PCT is where support for the instantly claimed therapeutic dosing regimen first appears.
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 1-4, 10, and 27-41 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.
Claims 1-4, 10, and 27-41 Indefinite – “about”
All claims recite or depend upon a claim that recites “about” a dose of the API. See, e.g., claim 1, which recites “0.1 mg to about 50 mg of Compound I…”. While “about” is generally considered broad, see MPEP 2173.05, one of ordinary skill in the art would not reasonably understand the metes and bounds of the claim term “about 50 mg” because Applicant has taken a term which already has some degree of variability to one of ordinary skill in the art, and ambiguously expanded it.
The Specification at 12, paragraph [0044], states that “about” means the “doses [administered] include … a specific dose, … or a range of the dose … that is recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose”. See Specification at 12, paragraph [0044]:
The term[] ''about'' … when used in connection with doses, amounts, or weight percentages of ingredients of a composition or a dosage form, include the value of a specified dose, amount, or weight percentage or a range of the dose, amount, or weight percentage that is recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent.
Specification at 12, paragraph [0044] (emphases added).
However, the specification provides exactly zero evidence of “a pharmacological effect” from any dose of the API administered. Applicant discloses exactly zero PK or PD data from these data in its possession. See Specification at 131-135. The single CFTR assay disclosed on page 132, paragraph [00190], represents data from an in vitro study that has no bearing on “a pharmacological effect” of this API in patients. Moreover, exactly zero patients were enrolled in Applicant’s trials. See Specification at 132, paragraph [00193]. Therefore, there is absolutely nothing in the Specification from which one could draw “a pharmacological effect” or “a pharmacological effect equivalent” from the doses administered. As a result, one of ordinary skill in the art would not understand what is presently claimed, in light of the specification.
Therefore, claims 1-4, 10, and 27-41 are rejected as indefinite.
Claims 39 and 41 Indefinite – Antecedent Basis Issues
Claim 39 recites the limitations of specifically designated active Compounds II, IV, V, VI, VII, XII, IX, and X. In a similar manner, claim 41 recites the limitations Compound III and Compound 111-d. There are insufficient antecedent bases for these limitations in the claims.
Applicant may remedy these issues by providing the chemical names for the actives and their chemical structures directly within the claim. See, e.g., original claim 24, in the claim set dated 08/01/2024, for acceptable claim language.
Accordingly, claims 39 and 41 are further rejected as indefinite, as there are insufficient antecedent bases for multiple claim limitations recited in the claims.
Claim 10 Indefinite – “heterozygous”
Independent claim 10 recites the limitation “wherein the patient is heterozygous” but does not state what particular gene mutation the patient is heterozygous for. As a result, the patient population carved out by the claim is unclear.
See claim 10:
A method of treating cystic fibrosis comprising administering to a patient in need thereof about 0.1 mg to about 50 mg of Compound I or an equivalent amount of a deuterated derivative or a pharmaceutically acceptable salt thereof daily, and wherein the patient is heterozygous and has one F508del mutation.
Claim 10.
See also, Specification at 10, paragraph [0034]:
As used herein, a patient who is “heterozygous” for a particular gene mutation has this mutation on one allele, and a different mutation on the other allele.
Specification at 10, paragraph [0034].
Importing the definition of heterozygous into the claim results in the following language:
A method of treating cystic fibrosis comprising administering to a patient in need thereof about 0.1 mg to about 50 mg of Compound I or an equivalent amount of a deuterated derivative or a pharmaceutically acceptable salt thereof daily, and wherein the patient has a particular gene mutation, and a different mutation on the other allele, and has one F508del mutation.
The claim does not identify a particular gene mutation, and a different mutation on the other allele, for the patient that being administered the active. Further, a patient that is homozygous for the F508del mutation “has one F508del mutation”, with “one F508del mutation” being on each allele. Accordingly, a patient homozygous for the F508del mutation is encompassed by the claim.
As a result, the patient population carved out by the claim is unclear, and claim 10 is further rejected as indefinite.
Claim Rejections - 35 USC § 112(d)
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.
Claim 35 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.
Claim 35 depends from claim 27. Both recite a pharmaceutical composition comprising about 0.1 mg to about 50 mg of Compound I or an equivalent amount of a deuterated derivative or a pharmaceutically acceptable salt thereof. The range is identical.
Accordingly, claim 35 is rejected as it fails to further limit the subject matter of the claim upon which it depends.
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 complies with the statutory requirements.
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 1-4, 10, and 27-41 Obvious over US’879 in view of Sabnis 2022, Stevers 2022, Hutt 2011, Wagner 2017, 2005 FDA Guidance and CAS Record for 2761295-59-2
Claim(s) 1-4, 10, and 27-41 is/are rejected under 35 U.S.C. 103 as being unpatentable over US’8791 in view of Sabnis 2022,2 Stevers 2022,3 Hutt 2011,4 Wagner 2017,5 2005 FDA Guidance,6 and CAS Record for 2761295-59-2.7
The claims are drawn to the medicinal use of active designated Compound I, its pharmaceutically acceptable salts and undisclosed deuterated derivatives. See Compound I:
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US’879 discloses CTFR modulating compounds such as its Example 2 compound at col. 42,
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Example 2 compound of US’879
US’879 teaches that its Example 2 active possesses a stunning ability to rescue the activity of CFTR made defective by the F508del mutation. See, e.g., US’879 at col 38, Table 1 and surrounding text, reproduced below. The example 2 active had a stellar EC50 in this role:
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US’879 at col 38.
US’879 discloses that compounds in this class were in critical need for patients with cystic fibrosis because of the lack of approved therapies that “target CFTR directly”. US’879 at col. 1.
See also, US’879 at col. 79, claim 11, reciting the active by name as the second compound. Claim 11 states that the active was encompassed by the general formula recited in claim 1. US’879, at col. 81, claim 14, teaches the cystic fibrosis indication for the US’879 Example 2 active. US’879 at claim 13 teaches the combination therapies for the US’879 Example 2 active with a number of different therapeutic agents, any of which could reasonably be a CFTR modulator, a CFTR corrector, or a CFTR potentiator, given the vague and open definition of these claim terms given in the instant Specification at 10-11, paragraphs [0035]-[0037].
US’879 at col. 35 teaches dosages for its actives (“Dosages of compounds of formula (I) or (II) employed in practicing the present invention will of course vary depending, e.g., on the particular condition to be treated, the effect desired and the mode of administration. In general, suitable daily dosages for administration by inhalation are of the order of 0.005-10 mg, while for oral administration suitable daily doses are of the order of 0.05-100 mg.”) (emphases added).
US’879 explains that the dosages administered represented a result effective variable that one of ordinary skill in the art at the time of filing could tune with respect to a desired therapeutic advantage. For example, US’879 discusses how isotopically labeling an API with deuterium may have an affect on the PK or PD of the drug. See US’879 at col. 20 (“Further, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent of a compound of the formula (I) or (II).”). It follows that when presented with a new API, one only need to conduct ordinary and routine experimentation to determine “dosage requirements” based upon a “therapeutic index” or a therapeutic advantage sought.
Yet, US’879 does not appear to expressly teach the instant macrocyclic CTFR modulating compound designated Compound I.
However, Sabnis 2022 at 1014 teaches that an important class of macrocyclic compounds were available to the public for use as CFTR modulators. These compounds bore the following general chemical structure:
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Sabnis 2022 explains that these compounds were useful for treating patients with cystic fibrosis. Given the very close structural similarity of these compounds and similar utilities to the compounds disclosed in US’879, one of ordinary skill in the art at the time of filing would correctly assume that these compounds were conformationally constrained, macrocyclic variants of the highly effective lead compounds disclosed in US’879.
Further, Stevers 2022 and Hutt 2011 both teach that macrocyclic CTFR modulating compounds were well-known within the art. Moreover, Wanger 2017 teaches a method of developing conformationally constrained, macrocyclic derivatives of known APIs that ordinary medicinal chemists at the time of filing used to develop these compounds, the method comprising running a computer program that would output key APIs to synthesize given an input API.
For example, see Stevers 2022 at Title (“Macrocycle-stabilization of its interaction with 14-3-3 increases plasma membrane localization and activity of CFTR”), and at Abstract (“Impaired activity of the chloride channel CFTR is the cause of cystic fibrosis. 14-3-3 proteins have been shown to stabilize CFTR and increase its biogenesis and activity. Here, we report the identification and mechanism of action of a macrocycle stabilizing the 14-3-3/CFTR complex. This molecule rescues plasma membrane localization and chloride transport of F508del-CFTR and works additively with the CFTR pharmacological chaperone corrector lumacaftor (VX-809) and the triple combination Trikafta®. This macrocycle is a useful tool to study the CFTR/14-3-3 interaction and the potential of molecular glues in cystic fibrosis therapeutics.”), and at 3, Fig. 1:
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Stevers 2022 at 3, Fig. 1.
See also, Hutt 2011 at 704, discussing how ordinary chemists at the time of filing constructed entire libraries of macrocyclic compounds mimicking known APIs useful for rescuing CFTR made defective by the F508del mutation:
Conformationally biased cyclic tetrapeptides20,21 and cyclic pseudotetrapeptides22 related to apicidin (3) have potent HDAC inhibitory properties. Considering the connection between HDAC inhibition and the improvement of ΔF508-CFTR trafficking, we screened our collection of >40 derivatives (see Table S1 in the Supporting Information), many of which inhibited class I HDACs in the nanomolar range, for their ability to restore the function of ΔF508-CFTR. Our collection of cyclic tetrapeptides was designed to cover a broad range of pharmacophoric configurations related to the natural product apicidin (3). The inclusion of β-amino acids (4–17) or triazoles in the backbone (18 and 19) biased the macrocycles toward conformational homogeneity. 20−22 Amino acids were varied at each of the four positions to survey different stereochemistries, backbone amide alkylations, side chain identities, and zinc coordinating groups. The tetrapeptides of interest (Chart 1; 4–19) were synthesized as described previously (Scheme S1 in the Supporting Information).20−22
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Hutt 2011 at 704.
See also, Wanger 2017, which discloses a computer program that an ordinary chemist at the time of filing could run wherein the program would propose a valid macrocyclic compound to synthesize based off an input API. See, e.g., Wagner 2017 at 1868, Figure 2.
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Wagner 2017 at 1868, Figure 2.
While the LigMac program discussed in Wanger 2017 was an older program, its outputs were able to match experimentally measured binding affinities, see, e.g., Wagner 2017 at 1866:
The comparison of experimental and calculated binding affinity for all targets is shown in Figure 1. Nearly all simulated values agree with experiment within 1kcalmol@1. Furthermore, the estimates of equivalent simulations are in general very similar. Simulations a) and b) are run to study the robustness of the simulation protocol with respect to small changes in the initial protein structure. Simulation c) mimics the design situation where the ligand’s conformation inside the protein binding pocket is not known a priori. An overview of the different simulations is given in Table 1. Detailed information about the calculated binding affinities can be found in Tables 2–6.
Wagner 2017 at 1866.
Therefore, it was well known at the time of filing that one could conformationally constrain a known API by using standard macrocyclic linkers, that medicinal chemists constructed entire libraries of these compounds that were useful for rescuing CFTR made defective by the F508del mutation, and that medicinal chemists could run programs that would propose a valid macrocyclic variant of a known API that would potentially be useful in the treatment of patients. Once an API was generated by such a program or constructed using simple routine experimentation of adjusting the linker in the same manner as the program would, these ordinary medicinal chemists understood how to test the compounds in standard assays and select the compounds that performed well enough for further testing in preclinical models and eventual first-in-human clinical trials.
Moreover, standard regulatory guidance existed for medicinal chemists to estimate starting doses for first-in-human clinical trials. See 2005 FDA Guidance at Title (“Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers”) and entire document. The method for dose estimation was standard, and took into account factors such as data derived in preclinical models and certain safety factors given a variety of standard factors known to medicinal chemists at the time of filing.
2005 FDA Guidance exemplifies that dose determination required only ordinary and routine experimentation well within the skills of an ordinary medicinal chemist at the time of filing.
Finally, see CAS Reg. No. 2761295-59-2 at 2, disclosing the following chemical that was made available to the public on 03/04/2022. The line on the second page of the document that states “ED Entered STN: 04 Mar 2022” means that this compound was publicly known at least by that date. Further, this compound is the active designated Compound I in the claims. Therefore, rather than having to design a new API to administer, the ordinary medicinal chemist at the time of filing could simply select it from a list of known macrocyclic compounds.
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CAS Reg. No. 2761295-59-2
Furthermore, one of ordinary skill in the art at the time of filing would recognize that the above compound was simply a macrocyclic derivative of the US’879 example 2 active because of the shared structural similarity between the two compounds, and the well-known use of macrocyclic derivatives in the field of cystic fibrosis treatments.
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Presented with the known need for additional therapeutics in this class, a medicinal chemist at the time of filing would be motivated to test the above compound in standard assays to confirm its in vitro efficacy as a CTFR modulating compound. The motivation would follow naturally from the very close structural similarity to the compelling lead compound, example 2 of US’879. The arrangement of atoms was indeed identical apart from the linker used to constrain the parent compound’s conformation.
Testing the compound’s activity in assays was standard for the ordinary medicinal chemist, and he could follow the guidance set forth in US’879 itself. Given that the compound was constructed from the compounds of US’879, there would be no reason for the medicinal chemist to deviate far from the teachings of US’879 that detailed how to administer the parent compound in pharmaceutical compositions to patients at a range of dosages. There was a reasonable expectation of success that the compound would function equally as well as a CFTR modulating compound in view of its very close shared structural similarity to the lead compound of US’879.
Designing a clinical trial to test the efficacy of the compound would require just following standard guidance from FDA regarding dose estimation, the clear guidance in US’879 regarding effective amounts, and ordinary and routine experimentation well within the skills of a medicinal chemist at the time of filing. Once safety was established, efficacy represented a result effective variable that the medicinal chemist could tune through routine experimentation.
Therefore, the medicinal chemist would have a reasonable expectation of success in treating cystic fibrosis by administering to a patient in need thereof 0.1 to about 50 mg of the compound represented by CAS Reg. No. 2761295-59-2, because it was just a macrocyclic derivative of the US’879 Example 2 active, and one would expect its dosing regimen to closely match the dosing for the US’879 Example 2 active. Any dosage adjustments would require only ordinary and routine experimentation, and the use of his ordinary skills as a medicinal chemist at the time of filing.
Accordingly, claim 1 was obvious at the time of filing.
Regarding the dosing recited in claims 2, 3, 4, 10, 27, 28, 29, 30, 31, 32, 33, 34, and 35, these doses all overlap with the dosing taught for the US’879 Example 2 active.
Accordingly, claims 2, 3, 4, 10, 27, 28, 29, 30, 31, 32, 33, 34, and 35 were obvious at the time of filing for the exact same reasons claim 1 was obvious at the time of filing.
Regarding claims 36, 37, 38, 39, 40, and 41, US’879 teaches that it was well known that cystic fibrosis treatment regimens included administering one or more additional therapeutic agents, particularly when the agent administered was one that stimulated insertion of del508 CFTR into the cell membrane. See, e.g., US’879 at claim 13; see also, US’879 at 34, teaching the combination with CFTR correctors such as VX-809 and VX-661, which appear to be embodiments of the additional therapeutic agents recited in at least claims 36-39, see annotated excerpt from US’879 at col. 34 below:
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Annotated excerpt from US’879 at col. 34.
One of ordinary skill in the art at the time of filing would have a reasonable expectation of success in adding standard combination therapies for CF into a pharmaceutical composition comprising the compound represented by CAS Reg. No. 2761295-59-2, because the compound was just a macrocyclic derivative of the US’879 Example 2 active, and one would expect its combination therapies to closely match those for the US’879 Example 2 active.
Accordingly, claims 36-39 were obvious at the time of filing.
Regarding claims 40 and 41, the examiner interprets these claims as possibly reciting combinations with administration of ivacaftor, which seems to align with the following sections of the Specification. See Specification at 132:
…the known Vertex potentiator ivacaftor (N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide or N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide)….
Specification at 132 (emphasis added).
See also, Specification at 6:
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Specification at 6.
Numerous references establish that it was well known that cystic fibrosis treatment regimens included administering one or more additional therapeutic agents, including ivacaftor. See, e.g. Stevers 2022 at 2, and the references it cites in the excerpt below:
The CFTR protein is a cyclic adenosine 5′-monophosphate (cAMP)–regulated transporter with anion channel activity that conducts Cl− on the apical surface of bronchial epithelial cells. The F508del-CFTR mutation is the most frequent cause of cystic fibrosis (CF)1. It codes for a mutant protein that is recognized as misfolded and retained in the endoplasmic reticulum but, if induced to traffic to the plasma membrane, it is almost fully functional2. Cell-based assays have identified compounds that facilitate the trafficking of F508del-CFTR to the plasma membrane. So far, the most effective compounds for F508del-CFTR have been pharmacological chaperones that bind to the mutant CFTR molecule and assist its correct folding1. To amplify the function of the corrected F508del-CFTR, the potentiator ivacaftor (Kalydeco®) that corrects the G551D mutation (which traffics normally but has defective gating) is included in combination with pharmacological chaperones3. There have been two approvals of such drug combinations that correct the trafficking of the F508del-CFTR, ivacaftor/lumacaftor (Orkambi®)4 in 2015 and ivacaftor/tezacaftor (Symdeko®)5 in 2018. More recently (2019), the triple combination ivacaftor/tezacaftor/elexacaftor (Trikafta®) has been approved6. The need for these combinations is that single molecules give low levels of correction and, although a new corrector VX-445 (elexacaftor) has been recently described that appears to give clinically significant levels of correction over a range of CFTR mutations, optimal results still require combination therapies7,8.
Stevers 2022 at 2.
Accordingly, claims 40-41 were obvious at the time of filing, for the same reasons stated for why claims 36-39 were obvious at the time of filing, and for the reasons stated above.
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’831
Claims 1-4, 10, and 27-41 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 37-41 of U.S. Patent No. US 12,269,831 B2,8 i.e., US’831. Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons.
First, see US’831 at 674, claims 37-41:
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US’831 at 674, claims 37-41.
Claim 41 teaches a method of treating cystic fibrosis comprising administering to a patient in need thereof an effective amount of the API recited in all of the instant claims. The method optionally has one or more additional therapeutic agents. Claim interpretation is required to determine what the claim means by “an effective amount”.
Now, see US’831 at 28, around lines 40-55, wherein it states:
The terms “effective dose” and “effective amount” are used interchangeably herein and refer to that amount of a compound that produces the desired effect for which it is administered (e.g., improvement in CF or a symptom of CF, or lessening the severity of CF or a symptom of CF). The exact amount of an effective dose will depend on the purpose of the treatment and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).
US’831 at 28.
Accordingly, US’831 states that the effective dose is obvious, in view of the compound itself. The only difference between the claims of US’831 and the instant claims is what US’831 states is obvious, i.e, the numeric recitation of effective doses.
Moreover, see US’831 at 82 (teaching a specific dose of 1 mg administered daily, and a range of 1 mg to 1000 mg administered daily). 1 mg administered daily in the method taught by claim 41 of US’831 directly reads on all pending claims – except for possibly instant claims 31-34, if the ambiguity regarding the claim term “about” is set aside.
Further, claim interpretation is required to determine what US’831 claim 41 means by “one or more additional therapeutic agents”.
Now see US’831 at cols. 139-143, and 146, item 168, which list the identical additional therapeutic agents recited in the instant claims.
Accordingly, one of ordinary skill in the art at the time of filing the application that led to the US’831 patent, and in possession of its subject matter, would at once envisage the inventions claimed in the instant application. Alternatively, one of ordinary skill in the art at the time of filing the application that led to the US’831 patent, and in possession of its subject matter, would have a reasonable expectation of success in obtaining the subject matter instantly claimed, because the US’831 directly states the effective amounts used for treating patients were obvious in view of the compound taught by its method recited in claim 41.
Accordingly, claims 1-4, 10, and 27-41 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 37-41 of US’831.
NSDP to US’242 in view of US’831
Claims 1-4, 10, and 27-41 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 6, 9, 15, 20, and 21 of copending Application No. 18/835,242,9 i.e., US’242, or the “US’242 application”, in view of US’831.
US’242 at claim 21 teaches administration of the same active in combination with one or more additional therapeutic agents. While the active administered is in crystalline form, administering a crystalline form of the active reads on all pending claims. See, e.g., US’242 at claims 1, 20, and 21, reproduced below (note that only a portion of claim 1 is excerpted below to save some space, but the text recites various crystalline forms):
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US’242 at claims 1, 20, and 21.
The only difference between the method recited in US’242 and the one instantly claimed is the numeric recitation of effective doses. However, as discussed above for the NSDP rejection of the claims to US’831, which is incorporated herein as reference, US’831 teaches that dosages for administration of the API were obvious over the compound itself.
Accordingly, one of ordinary skill in the art at the time of filing the US’242 application, and in possession of its subject matter, would have a reasonable expectation of success in obtaining the subject matter instantly claimed, because US’831 directly states the effective amounts used for treating patients were obvious in view of the compound taught by its method recited in claim 41.
This is a provisional nonstatutory double patenting rejection.
Secondary Consideration
Zero data regarding secondary considerations, such as such as surprising efficacy, were disclosed. Applicant reports no pharmacokinetics despite being in possession of such data, and discloses no results from its first-in-human studies, other than that “Compound I was generally safe and well-tolerated across all cohorts.” Specification at 135, paragraph [00201]. Each cohort consisted of healthy participants, and not patients. Accordingly, no efficacy data exist in the disclosure. Therefore, there appears to be nothing to consider regarding indica of non-obviousness.
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 Bala; Kamlesh Jagdis, et al., “Heterocyclic Compounds For The Treatment Of CF”, U.S. Patent No. US 9034879 B2, published 2015-05-19, Assignee Novartis AG, hereinafter “US’879”.
2 Sabnis, Ram W. "Novel Macrocyclic 1, 3, 4-Oxadiazoles as CFTR Modulators for Treating Cystic Fibrosis." ACS Medicinal Chemistry Letters 13.7 (May 27, 2022): 1014-1015, hereinafter “Sabnis 2022”. Cited in the IDS received 01/08/2024 as NPL cite 471.
3 Stevers, Loes M., et al. "Macrocycle-stabilization of its interaction with 14-3-3 increases plasma membrane localization and activity of CFTR." Nature Communications 13.1 (June 23, 2022): 3586, hereinafter “Stevers 2022”.
4 Hutt, Darren M., et al. "Potential Agents for Treating Cystic Fibrosis: Cyclic Tetrapeptides That Restore Trafficking and Activity of del-F508-CFTR." ACS medicinal chemistry letters 2 (2011): 703-707, hereinafter “Hutt 2011”.
5 Wagner, Vincent, et al. "Computational macrocyclization: from de novo macrocycle generation to binding affinity estimation." ChemMedChem 12.22 (2017): 1866-1872, hereinafter “Wagner 2017”. The supporting information for Wagner 2017 is also attached hereto.
6 Food and Drug Administration, “Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers”, July 2005, hereinafter “2005 FDA Guidance”.
7 CAS Record for 2761295-59-2 refers to the annexed STN Search for the index date of CAS Reg. No. 2761295-59-2. For those unfamiliar with STN searches, the annexed record states on page 2 “ED Entered STN: 04 Mar 2022”, which means that the scientists at CAS Registry indexed the compound on 04 Mar 2022. Therefore, the structure of the compound was publicly known at least by that date.
8 Clemens; Jeremy J., et al., “”, U.S. Patent No. US 12,269,831 B2, published 2025-04-08, Vertex Pharmaceuticals Incorporated Applicant, hereinafter “US’831”.
9 ANGELL, Paul Timothy, et al., “METHODS OF PREPARING AND CRYSTALLINE FORMS OF (6A,12A)-17-AMINO-12-METHYL-6,15-BIS(TRIFLUOROMETHYL)-13,19-DIOXA-3,4,18-TRIAZATRICYCLO[12.3.1.12,5]NONADECA-1(18),2,4,14,16-PENTAEN-6-OL”, U.S. Patent Application No. 18/835,242, published as U.S. Patent Application Publication No. US 20250320226 A1, filed 08/01/2024, Applicant Vertex Pharmaceuticals Incorporated, hereinafter “US’242”.
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