Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group I (i.e., claims 1-16 directed to a combination comprising (a) a compound of formula (I) and (b) one or more drugs selected from a compound of formula (IV), a S1PR modulator, and a STAT3 inhibitor) in the reply filed on December 5, 2024, is acknowledged. Additionally, Applicant’s election without traverse of Species A (i.e., a single and specific combination as compound BN201 as a compound of formula (I) and monomethyl fumarate as a compound of formula (IV) where the amount of both compounds are provided in a therapeutic amount; and Species B (i.e., a single and specific inflammatory neurological disease or condition as multiple sclerosis) in the reply filed on December 5, 2024, is acknowledged.
Please note that in light of the Examiner’s search, Species A is expanded to include where a compound of formula IV is dimethyl fumarate. Thus, instant claim 6 is hereby rejoined and examined.
Status of Claims
Claims 1-17 were originally filed on December 23, 2021.
The amendment received on December 23, 2021, amended claims 1, 3, and 5-17. The amendment received on December 5, 2024, amended claim 17. The amendment received on July 18, 2025, canceled claims 3-4; amended claims 1-2, 5-6, 11, and 15-16; and added new claims 18-22.
Claims 1-2 and 5-22 are currently pending and claims 1-2, 5-6, 11, 15-16, and 18-22 are under consideration as claim 17 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, and claims 7-10 and 12-14 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on December 5, 2024.
Priority
The present application claims status as a 371 (National Stage) of PCT/EP2020/068604 filed July 2, 2020, and claims priority under 119(a)-(d) to European Application No. 19382566.8 filed on July 3, 2019.
Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d) for European Application No. 19382566.8, which papers have been placed of record in the file. Please note that the European application is in English and therefore no further action is necessary.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on July 18, 2025 (2 IDSs) are being considered by the examiner. Please note that document FP8 has been crossed out and not considered because a copy of WO 2016/153957 A2 has not been provided as required under 37 CFR 1.98.
Maintained Rejections Necessitated by Amendment
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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 under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
103 - KSR Examples of 'Rationales' Supporting a Conclusion of Obviousness(Consistent with the "Functional Approach" of Graham)
Further regarding 35 USC 103(a) rejections, the Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) (KSR) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Also, a reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976).
Claims 1-2, 5-6, 11, 15-16, and 18-22 are rejected under 35 U.S.C. 103 as being unpatentable over Villoslada et al. WO 2012/028959 A1 (cited in the IDS received on 1/12/22) in view of Habboushe WO 2018/170319 A1 (cited in the IDS received on 9/26/24), alone or as evidenced by Levin et al., “Multiple Sclerosis”, Merck Manual, available online at https://www.merckmanuals.com/professional/neurologic-disorders/demyelinating-disorders/multiple-sclerosis-ms?query=multiple%20sclerosis, 14 pages (2023). Please note that the rejection has been updated in light of Applicants’ amendments to the claims.
Determination of the Scope and Content of the Prior Art (MPEP §2141.01)
For claims 1, and 15-16, with respect to a compound of formula (I) where R1 is phenyl substituted with halogen, R2 is 2-oxo-pyrrolidin-1-ylmethyl, and R3 is 2-methylpropyl as recited in instant claims 1 and 15-16:
Villoslada et al. teaches a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I-V and a pharmaceutically acceptable carrier (See Villoslada, [0016], [0020], [0130]-[0131]). This pharmaceutical composition is useful as a medicament to treat neurological conditions and nerve inflammatory conditions such as multiple sclerosis (See Villoslada, [0015]-[0016], [0025]-[0026], [0035], [0127], [0201]). VIlloslada et al. teaches that a compound of formula (I) is:
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where R1 is preferably 2-fluorophenyl, R2 is pyrrolidine-1-yl, and R3 is 2-methylpropyl (See Villoslada, [0065]-[0070], [0076], [0078]). A specific species of compound is depicted as a compound of formula III:
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(See Villoslada, [0081]). As such, Villoslada et al. teaches a pharmaceutical composition comprising a therapeutically effective amount of instant compound G79 and a pharmaceutically acceptable carrier useful to treat multiple sclerosis. Thus, the teachings of Villoslada et al. satisfy the claim limitations with respect to a compound of formula (I) where the compound of formula (I) is G79(BN201) as recited in instant claim 1, a compound of formula (I) and a pharmaceutically acceptable carrier in the pharmaceutical composition as recited in instant claim 15, and a first pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier as recited in instant claim 16.
For claims 1, 5-6, 15-16, and 21-22, with respect to a compound that is dimethyl fumarate (DMF) or monomethyl fumarate (MMF) as recited in instant claims 1, 5-6, 15-16, and 21-22:
Habboushe teaches treatment regimens for diseases such as multiple sclerosis that can be suitably treated with fumaric acid, its ester or salt thereof such as dimethyl fumarate (DMF), monomethyl fumarate (MMF) or combinations thereof (See Habboushe, [0007], [0014]). Habboushe also teaches a pharmaceutical composition comprising a combination of aspirin and a fumaric acid or an ester or salt thereof (See Habboushe, [0015]). Moreover, Habboushe teaches that the compositions can contain a pharmaceutically acceptable carrier (See Habboushe, [0034]). As such, Habboushe teaches a fumaric acid ester derivative where R5 is hydrogen or methyl and R6 is methyl, i.e., dimethyl fumarate or monomethyl fumarate. Thus, the teachings of Habboushe satisfy the claim limitations with respect to a compound that is dimethyl fumarate (DMF) or monomethyl fumarate (MMF) as recited in instant claims 1, 5-6, 15-16, and 21-22.
For claims 1 and 15-16, with respect to a combination of drugs a) and b) as recited in instant claim 1; with respect to where the combination of drugs are in the same composition as recited in instant claim 15; and with respect to where the combination of drugs are in separate compositions as recited in instant claim 16:
Villoslada et al. teaches the combined administration of compound G79 that involves AKT and ERK activation to PC12 cells with compound LY294002, which is a PI3K inhibitor, or compound PD98059, which is a MAPK kinase inhibitor, in order to evaluate if G79 modulates TrkA signaling pathway (See Villoslada, [0178]). Treatment with G79 and LY294002 or PD98059 resulted in a decrease in the number of differentiated cells when compared to G79 treatment alone (See Villoslada, [0179]). Although Villoslada et al. does not expressly teach that compound G79 is co-administered with DMF or MMF, Villoslada et al. suggests where compound G79 is combined with a second therapeutic compound where each would be administered in a therapeutically effective amount.
Habboushe teaches a method of treating multiple sclerosis by administering to the patient aspirin and fumaric acid or an ester or a salt thereof where the fumaric acid or ester or salt thereof is administered at about 300 mg to about 450 mg per day (See Habboushe, [0009]). The two drugs, aspirin and fumaric acid or ester or a salt thereof, can be administered separately or together, concurrently or sequentially (See Habboushe, [0009]). Thus, the teachings of Habboushe suggest a combination of DMF or MMF with a second therapeutic compound, either in separate compositions or together in one composition, where each compound would be administered in a therapeutically effective amount. Therefore, as will be further articulated below, an ordinary skilled artisan would be motivated with a reasonable expectation of success to substitute aspirin with compound G79 given that both compound G79 and DMF or MMF are known to treat multiple sclerosis.
For claims 2 and 18-20, with respect to where compound BN201 and DMF/MMF are in different dosage forms as recited in instant claim 2; with respect to where compound BN201 is in a parenteral dosage form as recited in instant claim 18; and with respect to where DMF/MMF is in an oral dosage form as recited in instant claims 19-20:
Villoslada et al. teaches that the compounds can be formulated into various pharmaceutical forms for administration purposes such as liquid compositions (e.g., solutions, suspensions, emulsions, etc.) (See Villoslada, [0131]). To prepare pharmaceutical compositions of the compounds, an effective amount of the compound as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier (See Villoslada, [0131]). These pharmaceutical compositions are in a dosage form suitable for administration orally, rectally, percutaneously, intrathecal, intravenous or by parenteral injection (See Villoslada, [0131]). For parenteral compositions, the carrier usually comprises sterile water, at least in part, though other ingredients, for example, to aid solubility may be included (See Villoslada, [0131]). Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution (See Villoslada, [0131]). Thus, the teachings of Villoslada et al. teach the BN201 compound being in a parenteral dosage form, e.g., a solution, thereby satisfying the claim limitation as recited in instant claim 18.
Habboushe teaches administering one or more tablets orally to a patient in need of treatment of multiple sclerosis where each tablet comprises a first portion comprising a first amount of aspirin and a second portion comprising a second amount of fumaric acid or an ester or a salt thereof where the second portion is formulated for dissolving in the stomach, intestines or further distal in the GI tract of the subject (See Habboushe, [0020]). Thus, the teachings of Habboushe teach DMF/MMF being in an oral dosage form, e.g., a tablet, thereby satisfying the claim limitation as recited in instant claims 19-20. Furthermore, since Villoslada teaches that compound BN201 can be in a parenteral dosage form, e.g., a solution, and Habboushe teaches that DMF/MMF are in an oral dosage form, e.g., a tablet, it necessarily follows that the two compounds are in different dosage forms as recited in instant claim 2.
For claims 11 and 15-16, with respect to where a therapeutically effective amount of a) where the amount is effective to treat a disorder that results in the destruction or degeneration of neurons, axons, or myelin in a human:
As discussed supra, Villoslada et al. teaches a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I-V and a pharmaceutically acceptable carrier (See Villoslada, [0016], [0020], [0130]-[0131]). This pharmaceutical composition is useful as a medicament to treat neurological conditions and nerve inflammatory conditions such as multiple sclerosis (See Villoslada, [0015]-[0016], [0025]-[0026], [0035], [0127]). Moreover, Villoslada et al. defines an effective amount of the compounds of formulas I-V in the range from 0.01 mg to 50 g per day (See Villoslada, [0110]). Plus, Villoslada et al. administered G79 in an amount of 40 mg/kg or 100 mg/kg to animals induced to suffer from multiple sclerosis (See Villoslada, [0203]). As evidenced by Levin et al., the pathophysiology of multiple sclerosis includes localized areas of demyelination (plaques) occur, with destruction of oligodendroglia, perivascular inflammation, and chemical changes in lipid and protein constituents of myelin in and around the plaques (See Levin, pg. 2, 3rd paragraph). As such, multiple sclerosis constitutes a disorder that results in the destruction or degeneration of myelin in a human.
Additionally and/or alternatively, even if Villoslada et al. did not expressly teach a therapeutically effective amount of compound BN201 where the amount is effective to treat multiple sclerosis, since Villoslada et al. teaches therapeutically effective amounts of compound BN201, the functional property (i.e., to treat a disorder that results in the destruction or degeneration of neurons, axons, or myelin in a human) of the amount as claimed and the known amount would necessarily read upon the same. The discovery of a previously unappreciated property of a prior art composition, or a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer. Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus, the claiming of a new functional property (i.e., to treat a disorder that results in the destruction or degeneration of neurons, axons, or myelin in a human) which would necessarily read upon the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 4333 (CCPA 1977). Thus, the teachings of Villoslada et al. satisfy the claim limitation with respect to where compound BN201 is present in the pharmaceutical composition in a therapeutically effective amount where the amount is effective to treat a disorder that results in the destruction or degeneration of neurons, axons, or myelin in a human as recited in instant claims 11 and 15-16.
For claims 11 and 15-16, with respect to where a therapeutically effective amount of b) where the amount is effective to treat a disorder that results in the destruction or degeneration of neurons, axons, or myelin in a human:
Habboushe teaches that the fumaric acid or an ester or salt thereof can be administered in a significantly lower dose such as 360 mg, 400 mg, or 420 mg per day without comprise of the treatment outcome (See Habboushe, [0008]). Habboushe teaches a method of treating multiple sclerosis by administering to the patient aspirin and fumaric acid or an ester or a salt thereof where the fumaric acid or ester or salt thereof is administered at about 300 mg to about 450 mg per day (See Habboushe, [0009]). Moreover, Habboushe teaches that the amount of fumaric acid or ester or salt thereof is about 180 mg (See Habboushe, [0013]). As evidenced by Levin et al., the pathophysiology of multiple sclerosis includes localized areas of demyelination (plaques) occur, with destruction of oligodendroglia, perivascular inflammation, and chemical changes in lipid and protein constituents of myelin in and around the plaques (See Levin, pg. 2, 3rd paragraph). As such, multiple sclerosis constitutes a disorder that results in the destruction or degeneration of myelin in a human.
Additionally and/or alternatively, even if Habboushe did not expressly teach a therapeutically effective amount of DMF or MMF where the amount is effective to treat multiple sclerosis, since Habboushe teaches therapeutically effective amounts of DMF or MMF, the functional property (i.e., to treat a disorder that results in the destruction or degeneration of neurons, axons, or myelin in a human) of the amount as claimed and the known amount would necessarily read upon the same. The discovery of a previously unappreciated property of a prior art composition, or a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer. Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus, the claiming of a new functional property (i.e., to treat a disorder that results in the destruction or degeneration of neurons, axons, or myelin in a human) which would necessarily read upon the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 4333 (CCPA 1977). Thus, the teachings of Habboushe satisfy the claim limitation with respect to where DMF or MMF is present in the pharmaceutical composition in a therapeutically effective amount where the amount is effective to treat a disorder that results in the destruction or degeneration of neurons, axons, or myelin in a human as recited in instant claims 11 and 15-16.
For claim 16, with respect to a package or kit comprising (i) a first pharmaceutical composition, (ii) a second pharmaceutical composition, and (iii) instructions for the use in combination of i) and ii):
It is noted that Villoslada et al. or Habboushe do not teach a package or kit comprising each compound. However, as discussed supra, Villoslada et al. teaches a pharmaceutical composition comprising a therapeutically effective amount of a compound of instant formula (I) and a pharmaceutically acceptable carrier thereby constituting a first pharmaceutical composition, and Habboushe teaches a pharmaceutical composition comprising a therapeutically effective amount of DMF or MMF and a pharmaceutically acceptable carrier thereby constituting a second pharmaceutical composition. Moreover, Habboushe teaches a pharmaceutical composition comprising a combination of compounds where the combination of compounds are present together in the same composition or in separate compositions. Since each reference teaches a first pharmaceutical composition and a second pharmaceutical composition where each composition is to be administered to a subject in a dosage form such as a form suitable for oral or parenteral administration (See Villoslada, [0131]; Habboushe, [0017], [0020]), it would necessarily follow that the compositions are packaged and/or stored in a container thereby constituting a package or kit of parts as recited in instant claim 16. Otherwise there would be no way to store the compositions prior to administration.
Additionally, regarding the instructions, it is noted that the Federal Circuit found that in addressing a method claim whose first step was drawn to the prior art method of administering metazalone AND an additional prescribing step addressing the inherent result of taking metaxalone with food, i.e., an increase in the bioavailability of the drug, the Federal Circuit in the King Case, 95 USPQ2d at 1842-43, analogized these facts to those faced by written instructions and their effect on compositions claims: “In an analogous context, we have held that ‘[w]here the printed matter is not functionally related to the substrate, the printed matter will not distinguish the invention from the prior art in terms of patentability. Citing In re Gulack, 703 F.2d 1381, 1385 (Fed. Cir. 1983). In holding the metaxalone administering method anticipated, the Federal Circuit established the following relevant inquiry as to whether a prescribing step imparts patentability: "...whether the additional instructional limitation ... has a "new and unobvious functional relationship” with the known method of administering metaxalone with food.“ See In re Ngai, 367 F.3d at 1338 (quoting In re Gulack, 703 F.2d at 1386). As in the “King" case, the instant pharmaceutical composition comprises instructions for diluting and preparing the pharmaceutical composition for administration to a human that merely recite information regarding properties that are inherent to the prior art composition, or information that constitutes product-by-process (as previously discussed). Thus, these instant prescribing limitation is similarly not patentably distinguishing and merely is an informing limitation that provide no novelty to the claimed composition.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims (MPEP §2141.012)
Villoslada et al. and Habboushe do not expressly teach a combination of a compound BN201 and DMF or MMF as recited in instant claims 1, 5-6, and 21-22, a single pharmaceutical composition comprising the combination of claim 1 and a pharmaceutically acceptable carrier where each compound is present in a therapeutically effective amount as recited in instant claim 15, and a package or kit comprising a first pharmaceutical composition comprising a therapeutically effective amount of compound BN201 and a pharmaceutically acceptable carrier, a second pharmaceutical composition comprising a therapeutically effective amount of DMF or MMF and a pharmaceutically acceptable carrier as recited in instant claim 16. However, the combination of Villoslada et al. and Habboushe cure these deficiencies by constituting the combination of prior art elements according to known methods to yield predictable results and/or a simple substitution of one known element for another to obtain predictable results and/or some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
Finding of Prima Facie Obviousness Rationale and Motivation (MPEP §2142-4143)
With respect to a combination of a compound BN201 and DMF or MMF as recited in instant claims 1, 5-6, and 21-22, a single pharmaceutical composition comprising the combination of claim 1 and a pharmaceutically acceptable carrier where each compound is present in a therapeutically effective amount as recited in instant claim 15, and a package or kit comprising a first pharmaceutical composition comprising a therapeutically effective amount of compound BN201 and a pharmaceutically acceptable carrier, a second pharmaceutical composition comprising a therapeutically effective amount of DMF or MMF and a pharmaceutically acceptable carrier as recited in instant claim 16, it would have been prima facie obvious to one of ordinary skill in the art as of the effective filing date of the instant application to modify the teachings of Habboushe and substitute a combination of a therapeutically effective amount of compound BN201 instead of aspirin, a therapeutically effective amount of DMF or MMF, and a pharmaceutically acceptable carrier where the combination is present in the same or separate compositions in order to treat multiple sclerosis. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because a pharmaceutical composition comprising a therapeutically effective amount of compound BN201 was known to be treat multiple sclerosis as taught by Villoslada et al. One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that a combination of a therapeutically effective amount of aspirin and a therapeutically effective amount of DMF or MMF of Habboushe was administered to treat multiple sclerosis in the same or separate compositions. Therefore, substituting a therapeutically effective amount of compound BN201 instead of aspirin in the combination would support the treatment of multiple sclerosis by constituting a simple substitution of one known element for another to obtain predictable results and/or some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
Additionally and/or alternatively, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to combine the teachings of Villoslada et al. and Habboushe and administer to a subject a therapeutically effective amount of compound BN201 in combination with a therapeutically effective amount of DMF or MMF in order to treat multiple sclerosis in the subject who is diagnosed with multiple sclerosis where the combination of compounds is in the same or separate compositions. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because administering a pharmaceutical composition comprising a therapeutically effective amount of compound BN201 and a pharmaceutically acceptable carrier to a subject was known to treat multiple sclerosis as taught by Villoslada et al.; and because administering a pharmaceutical composition comprising a therapeutically effective amount of DMF or MMF and a pharmaceutically acceptable carrier to a subject was known to treat multiple sclerosis as taught by Habboushe. One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that a therapeutically effective amount of compound BN201 of Villoslada et al. and a therapeutically effective amount of DMF or MMF of Habboushe were administered to a subject diagnosed with multiple sclerosis to treat multiple sclerosis. Therefore, "it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose… [T]he idea of combining them flows logically from their having been individually taught in the prior art." (MPEP 2144.06). In re Susi, 58 CCPA 1074, 1079-80, 440 F.2d 442, 445, 169 USPQ 423, 426 (1971); In re Crockett, 47 CCPA 1018, 1020-21, 279 F.2d 274, 276-77, 126 USPQ 186, 188 (1960). As the court explained in Crockett, the idea of combining them flows logically from their having been individually taught in prior art. Therefore, since each of the references teach compounds that are effective in treating multiple sclerosis, it would have been obvious to combine the two compounds with the expectation that such a combination would be effective in treating multiple sclerosis. Thus, combining them flows logically from their having been individually taught in prior art.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Applicants’ Arguments
Applicants contend that the claimed invention is nonobvious because (1) whether two drugs that act on different metabolic pathways to treat a disease can be used in concert, or are not unduly toxic when given in combination to a human, is a very complex question, especially since the mechanism by which mono/dimethylfumarate works is currently unknown with a long list of identified negative drug interactions as described in Attachment A (i.e., Drugs.com excerpt), and thus, if a researcher does not known the pathway that a drug modifies to effect treatment, there is no way that it would obvious prior to testing how the drug with the unknown mechanism of action would interact with another drug with a known mechanism of action to treat the same disease (See Applicant’s Response received on 7/18/25, pg. 9-10); (2) the claimed invention of a combination of BN201 with DMF or MMF exhibits the unexpected results of achieving potent synergistic therapeutic effects for the treatment of inflammatory ophthalmic and/or neurological diseases in vitro and in vivo as demonstrated in instant Examples 3 and 6 and Figures 3 and 5 (See Applicant’s Response received on 7/18/25, pg. 11-14); (3) the teachings of Villoslada’s Example 7 do not demonstrate a combination therapy of BN201 with inhibitor compounds, LY294002 or PD98059, for treatment of a human, but rather demonstrates that LY294002 or PD98059 reverse the activity of compound BN201 (See Applicant’s Response received on 7/18/25, pg. 14-16); and (4) the teachings of Habboushe teach that the combination of aspirin with fumarate resulted in an improved pharmacokinetic (PK) effect of fumarate and reduced side effects, and not improvement in the treatment of multiple sclerosis (See Applicant’s Response received on 7/18/25, pg. 16).
Response to Arguments
Applicant's arguments filed 7/18/25 have been fully considered but they are not persuasive for the following reasons.
In response to Applicant’s first argument, i.e., whether two drugs that act on different metabolic pathways to treat a disease can be used in concert, or are not unduly toxic when given in combination to a human, is a very complex question, especially since the mechanism by which mono/dimethylfumarate works is currently unknown with a long list of identified negative drug interactions as described in Attachment A (i.e., Drugs.com excerpt), and thus, if a researcher does not known the pathway that a drug modifies to effect treatment, there is no way that it would obvious prior to testing how the drug with the unknown mechanism of action would interact with another drug with a known mechanism of action to treat the same disease, it is found unpersuasive. Pursuant to MPEP 2143.02(II), obviousness does not require absolute predictability, however, at least some degree of predictability is required. Evidence showing there was no reasonable expectation of success may support a conclusion of nonobviousness. In re Rinehart, 531 F.2d 1048, 189 USPQ 143 (CCPA 1976). In the instant case, Villoslada expressly teaches that compound including compound BN201 would be useful for the treatment of neurological disorders such as multiple sclerosis. Habboushe expressly teaches that a combination of aspirin and fumaric acid and derivatives thereof including DMF and MMF would be useful for the treatment of multiple sclerosis. As such, irrespective of the mechanism by which each compound treats multiple sclerosis and without evidence demonstrating that the mechanism of action by which two compounds treat a disease/disorder/condition would render the combination of the compounds unobvious, e.g., one compound acting via mechanism 1 would impede or have a negative impact on the mechanism of action of compound 2, the combined prior art suggests each compound individually treats multiple sclerosis. Furthermore, Applicants have provided no evidence in the case law and/or MPEP, to suggest that the mechanism by which a therapeutic agent treats a disease/disorder/condition is a necessary criteria in order for an ordinary skilled artisan to have the requisite expectation of success to, at a minimum, combine the agents to treat the same disease/disorder/condition. As stated supra, the standard for obviousness does not require absolute predictability. Rather, at least some degree of predictability is required. Applicants are respectfully reminded that the Patent Office is separate from the FDA. Requiring the art to recognize a specific combination of compounds as a safe combination would likely be a concern for FDA approval. However, no known drug interaction between two compounds does not per se render that combination of compounds nonobvious without evidence to the contrary. Although Applicants provide a list of known negative drug interactions for DMF, none of the listed compounds is compound BN201. Nor has Applicant provided evidence that BN201 being a serum-glucocorticoid (SGK2) agonist would exhibit a negative interaction with DMF/MMF. For example, Applicants have not indicated that any of the listed compounds known to negatively interactive with DMF are SGK2 agonists. Therefore, contrary to Applicant’s argument, the combination of Villoslada and Habboushe provide the requisite degree of predictability since both teach that each compound treats the same disease, i.e., multiple sclerosis, without evidence to the contrary.
In response to Applicant’s second argument, i.e., the claimed invention of a combination of BN201 with DMF or MMF exhibits the unexpected results of achieving potent synergistic therapeutic effects for the treatment of inflammatory ophthalmic and/or neurological diseases in vitro and in vivo as demonstrated in instant Examples 3 and 6 and Figures 3 and 5, it is found unpersuasive. Pursuant to MPEP 716.02(d), whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” Furthermore, MPEP 2145 states, in order for evidence of secondary considerations to be accorded substantial weight, there must be a nexus, i.e., a legally and factually sufficient connection or correspondence between the submitted evidence and the claimed invention. Fox Factory, Inc. v. SRAM, LLC, 944 F.3d 1366, 1373, 2019 USPQ2d 483355 (Fed. Cir. 2019), cert. denied, 141 S.Ct. 373 (2020). "A presumption of nexus requires both that the product embodies the invention and is coextensive with it." Volvo Penta of the Americas, LLC v. Brunswick Corp., 81 F.4th 1202,1211-12, 2023 USPQ2d 1000 (Fed. Cir. 2023). In the instant case, Applicants are respectfully reminded that the claimed inventions are directed to products, i.e., a combination of compound BN201 and DMF/MMF, a composition comprising both compound BN201 and DMF/MMF, and a kit comprising a first composition comprising compound BN201 and a second composition comprising DMF/MMF. Notably, the claimed combination and claimed kit do not require the two compounds to be present in the same composition. The combination and kit encompass both compounds separate, in fact, expressly separate in the kit claim of claim 16. In other words, the scope of the claimed combination and kit encompass where a vial of BN201 is sitting on a shelf in a pharmacy, for example, and a second vial of DMF/MMF is sitting on the shelf next to BN201. The two vials sitting next to each other do not structurally provide the alleged unexpected results. Rather, the alleged unexpected results are dependent upon the intended use of the compounds when administered in a specific manner to treat a patient. Thus, with respect to the claimed combination and kit, there is a lack of nexus between the required structures of the claimed combination and kit and the alleged unexpected result of achieving potent synergistic therapeutic effects.
However, even for the claimed composition, which requires therapeutically effective amounts of both compound BN201 and DMF/MMF in the same composition, the evidence provided by Applicant does not clearly support a finding of unexpected synergy. Pursuant to MPEP 716.02(a), “[a] greater than expected result is an evidentiary factor pertinent to the legal conclusion of obviousness ... of the claims at issue." In re Corkill, 711 F.2d 1496, 226 USPQ 1005 (Fed. Cir. 1985). Evidence of a greater than expected result may also be shown by demonstrating an effect which is greater than the sum of each of the effects taken separately (i.e., demonstrating “synergism"). Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). However, a greater than additive effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected. Applicants must further show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991). In the instant case, Applicants point to Examples 3 and 6 and Figures 3 and 5 as demonstrating that the combination of compound BN201 and DMF/MMF exhibits synergistic therapeutic effects. Example 3 compared the therapeutic effect of each compound individually and combined together in mice suffering from EAE (See instant, Example 3). The mice were administered DMF, BN201, or a combination thereof once a day for 6 days per week at suboptimal dosages (10 mg/kg for DMF orally and 25 mg/kg for BN201 via injection) (See instant, Example 3). The specification states that the experiment as shown in Figure 3, demonstrates that BN201 and DMF, individually, at suboptimal doses suffered EAE similar to those mice treated with placebo, but the combination of suboptimal doses of the two compounds ameliorated the course of the disease in a significant matter by day 34-38 (See Figure 3 values with asterisks indicating statistical significance) (See instant, Example 3). Thus, the specification states that the combination of the two compounds shows a synergistic effect for ameliorating the course of EAE. However, it is not readily apparent from the data provided in Figure 3, (1) that the combination of compounds demonstrates a greater than additive effect, and (2) what the provided statistical significance is relative to; meaning, statistically significant relative to the control, or to each individual compound, or all three. Given the close proximity to the DMF line at several days indicated as statistically significant, i.e., days 19-21 and 25-28 at a minimum (interpreting that the day numbers depicted in Figure 3 on the x-axis correspond to days 34-36 and 40-43 given that the first 15 days the mice were induced with EAE), it is unclear how these values statistically demonstrate a synergistic effect, i.e., a greater than additive effect.
Similarly, in Example 6 in the instant specification, it is not readily apparent from the data provided that the observed effect is synergistic. Example 6 compares the effects of a combination of compound BN201 and MMF with each compound individually in a neuroprotective assay (See instant, Example 6). Here, cells were pre-incubated with varying concentrations of the compounds individually or together, and then hydrogen peroxide was added to induce stress (See instant, Example 6). Then the medium was changed to MTT and cell viability determined (See instant, Example 6). The specification states that the cell viability, provided as a percentage compared to the control, is increased after pre-treatment with the combination of compound compared to the individual compounds as depicted in Figure 5 thereby demonstrating that the combination exerts a synergistic neuroprotective effect (See instant, Example 6). However, statistical significance is only indicated for 4 specific concentration values, i.e., 3, 10, 20 and 40 µM (See instant, Figure 5). Notably, when the concentration of the compounds was at 5 µM, statistically significance was not observed (See instant, Figure 5). As such, the concentration of each compound being at least 10 µM appears critical in achieving the alleged unexpected results. None of the claimed inventions recite specific concentration values. Only the composition of claim 15 and the kit of claim 16 require a therapeutically effective amount to treat a disorder that results in the destruction or degeneration of neurons, axons or myelin in a human for each compound, but no indication what those amounts are. Notably, a therapeutically effective amount does not per se correlate to an amount that results in a synergistic therapeutic effect. Furthermore, as in Figure 3, it is not readily apparent that the improved cell viability for the combination of compounds correlates to a greater than additive effect of each compound individually, especially, given the close proximity of the bars at 10 µM. Therefore, clarification regarding whether the data depicted in Figures 3 and 5 correlates to a greater than additive effect is respectfully requested. Moreover, assuming arguendo, that synergy is confirmed, the scope of the claimed inventions are not commensurate in scope with the unexpected results. Thus, contrary to Applicant’s argument, the claimed inventions are not rendered unobvious in light of unexpected results.
In response to Applicant’s third argument, i.e., the teachings of Villoslada’s Example 7 do not demonstrate a combination therapy of BN201 with inhibitor compounds, LY294002 or PD98059, for treatment of a human, but rather demonstrates that LY294002 or PD98059 reverse the activity of compound BN201, it is found unpersuasive. Pursuant to MPEP 2123 (II), “[d]isclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994). In the instant case, it is acknowledged that Example 7 in Villoslada evaluates if G79 modulates TrkA signaling pathway by combining compound G79 with AKT or ERK pathway inhibitors. However, even though the number of differentiated cells is reduced relative to compound G79 alone thereby constituting an inferior result does not per se correlate to Villoslada failing to suggest a combination therapy.
Alternatively, assuming arguendo, that such teaching in Villoslada does not suggest a combination therapy, the rejection utilizes multiple KSR rationales to render the claimed invention obvious. Pursuant to MPEP 2144.06, it states that, "[it] is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted). In the instant case, Villoslada teaches compound BN201 is useful to treat multiple sclerosis and Habboushe teaches DMF or MMF is useful to treat multiple sclerosis thereby constituting compositions each of which is taught by the prior art to be useful for the same purpose, one of ordinary skill in the art would be motivated with a reasonable expectation of success to form a third composition to be used for the very same purpose. Therefore, the Examiner has established a prima facie case of obviousness, and Applicants have not provided evidence rebutting that such a combination would have a negative effect on each ingredient. Thus, even if Villoslada does not expressly teach a combination of compound BN201 with another compound, an ordinary skilled artisan would be motivated with a reasonable expectation of success to combine compound BN201 and DMF or MMF because both compounds are known to be used for the same purpose.
In response to Applicant’s fourth argument, i.e., the teachings of Habboushe teach that the combination of aspirin with fumarate resulted in an improved pharmacokinetic (PK) effect of fumarate and reduced side effects, and not improvement in the treatment of multiple sclerosis, it is found unpersuasive. Pursuant to MPEP 2141, “[a] prior art reference must be considered in its entirety, i.e., as a whole, including portions that would lead away from the claimed invention. W.L. Gore & Assoc., Inc. v. Garlock, Inc., 721 F.2d 1540, 220 USPQ 303 (Fed. Cir. 1983), cert. denied, 469 U.S. 851 (1984). In the instant case, as discussed in the rejection supra, Habboushe expressly teaches that DMF and its metabolite, MMF, are effective treatments for relapse-remitting multiple sclerosis (RMMS) (See Habboushe, [0006]). However, DMF and MMF administration comes with a likely side effect of cutaneous flush (See Habboushe, [0006]). As such, Habboushe sought a formulation comprising DMF or MMF in a dosage form that would result in reduced side effects without compromising treatment outcome including treatment of multiple sclerosis (See Habboushe, [0007]). The fact that Habboushe sought a formulation with an improved pharmacokinetic (PK) effect of fumarate and reduced side effects for the treatment multiple sclerosis in a subject does not preclude that Habboushe teaches treating multiple sclerosis by administering DMF or MMF. In fact, a formulation comprising DMF or MMF in a dosage form that results in an improved pharmacokinetic (PK) effect of fumarate and reduced side effects would arguably correspond to an improved therapeutic effect, i.e., an improved additive therapeutic effect, of treating multiple sclerosis when this improved DMF or MMF formulation is combined with compound BN201 taught by Villoslada. Thus, contrary to Applicant’s argument, the teachings of Habboushe are relevant to DMF or MMF useful for the treatment of multiple sclerosis.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be di