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
This Application is a 371 of PCT/FI2020/050475, filed July 30, 2020, and claims foreign priority to FI20195595, filed July 1, 2019 in Finland.
Claim Status
Claims 1-2, 6, 8-15 and 40 are currently pending. Pursuant to a Restriction requirement mailed Nov. 8, 2024, claims 1-2 are currently active and subject to examination and claims 6, 8-15 and 40 are withdrawn.
Claim Rejections - 35 USC § 103- Previously Presented
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.
The rejection of claim(s) 1-2 under 35 U.S.C. 103 as being unpatentable over Segreti et al. (Journal Of Pharmacology And Experimental Therapeutics, Vol. 325, No. 1, April 2008, p. 331-340) in view of Kurkela et al. (US 6399610 B1) and Yan et al. (CN 104414963 A; Published March 18, 2015) is maintained.
Response to Arguments
The Applicant argues that (1) the prior art does not teach or suggest ocular administration (Remarks, p. 6); (2) There are unique benefits of ocular administration including rapid systemic absorption comparable to IV administration (id., p. 6-8); (3) there are structural and pharmacological differences between levosimendan and compound (I) (id., p. 9-10); and (4) there is no motivation to combine because ocular deliver for systemic administration is rare, most ocular drugs are for treating eye disease locally, and that the references do not establish that compound (I) could achieve sufficient systemic levels while avoiding irritation (id., p. 9). These arguments were fully considered but are not persuasive.
The prior art does teach/ suggest ocular administration because OR-1896 is the active metabolite of levosimendan as shown by Segreti, and it is known to deliver levosimendan transmucosally as shown by Kurkela. The conjunctiva of the eye is a mucosal surface, and the mechanism of drug absorption through the mucosa should be similar across mucosal surfaces. Kurkela specifically teaches that administering levosimendan via a mucosal surface delivers therapeutically effective and steady serum levels to the patient for the treatment of heart failure:
It has now been found that therapeutically effective and steady serum levels of levosimendan are rapidly achieved by administering levosimendan transmucosally, preferably to oral or nasal mucosa. Furthermore, it has been found that by administering levosimendan transmucosally the occurence of undesired side effects such as headache and palpitation connected to the oral administration of levosimendan can be reduced or totally avoided.
Kurkela, Specification, col. 1, lines 40-44;
The transmucosal administration of levosimendan or a pharmaceutically acceptable salt thereof can be accomplished generally by contacting an intact mucous membrane with a source of levosimendan or a pharmaceutically acceptable salt thereof, and maintaining said source in contact with said mucous membrane for a sufficient time period to induce the desired therapeutic effect.
Kurkela, Specification, col. 2, lines 28-34.
While the applicant tries to argue that Kurkela is silent as to ocular administration of levosimendan (Remarks, p. 7), this argument is formalistic because Kurkela teaches the principle that transmucosal delivery works, not a closed list of which mucosal surfaces to use. Moreover, Yan specifically teaches that levosimendan can be formulated as eye drops, which strengthens the argument that one of ordinary skill in the art would reasonably expect that transmucosal delivery through the conjunctiva of the eye would work.
One of ordinary skill in the art would also reasonably expect that there would be rapid systemic delivery of compound (I) after contacting the conjunctival surface with a therapeutically effective amount of compound (I) based on the teachings of Segreti, Kurkela, and Yan. As stated above, Segreti specifically teaches that compound (I) is the active metabolite of levosimendan and Kurkela specifically teaches that systemic delivery of levosimendan can be achieved by transmucosal delivery. As such, one of ordinary skill in the art would reasonably expect that compound (I) could be delivery systemically by transmucosal delivery, particularly through the conjunctiva, because Yan teaches levosimendan eye drops.
While there are structural and pharmacological differences between levosimendan and compound (I), this does not undermine the reasonable expectation of success. Segreti teaches that compound (I) is the active metabolite of levosimendan and that both drugs produce myocardial and hemodynamic therapeutic effects. While the degree of the effect might be slightly different depending on the measured parameter, both drugs produce the same therapeutic effects qualitatively and they do not have fundamentally different mechanisms. There are strong structural and functional relationships between the parent drug and the active metabolite, and the minor variations in activity do not undermine the reasonable expectation that the parent drug and active metabolite behave similarly.
Overall, there is a strong argument that one of ordinary skill in the art would have a reasonable expectation of success to administer compound (I) by an ocular route. Motivation is not required as the KSR standard applies here: “the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 398, 415-416, 82 USPQ2d 1385, 1395 (2007)). The Applicant does not show any unexpected results or something special about the ocular formulation that is not predictable. The Applicant does not present evidence that an ordinary artisan would not believe that ocular delivery would work. The Applicant does not show any data demonstrating that compound (I) behaves differently than levosimendan in mucosal absorption.
Reiterated Rejection
Claim 1 is directed towards:
A method for administration of (R)-N-[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3- pyridazinyl)phenyl]acetamide (I) to a patient in need thereof comprising administering (R)- N-[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]acetamide (I) to a patient by ocular administration.
It is commonly known in the art that (R)-N-[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3- pyridazinyl)phenyl]acetamide (I), known as OR-1896, is the active metabolite of levosimendan and exerts similar effects. For example, Segreti teaches that levosimendan is metabolized to OR-1896 in humans and that both levosimendan and OR-1896 produce dose dependent reductions in blood pressure and peripheral resistance:
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Segreti, Abstract.
While Segreti does not teach either OR-1896 or levosimendan administration by a transmucosal route, one of ordinary skill in the art would have a reasonable expectation of success to administer OR-1896 by a transmusocal route because Segreti teaches OR-1896 is the active metabolite of levosimendan with the same therapeutic activity and the administration of levosimendan by a transmucosal route by contacting a mucous membrane with levosimendan is commonly known in the art. For example, Kurkela teaches a method of administering levosimendan transmucosally:
Accordingly, the object of the invention is to provide a method for administering transmucosally, i.e. to and across a mucosal surface, levosimendan or a pharmaceutically acceptable salt thereof. The mucosal surface is preferably oral or nasal mucosa such as the buccal mucosa, the sublingual mucosa, the sinuidal mucosa, the gum, or the inner lip.
Kurkela, Specification, column 1, lines 54-60.
While Kurkela does not teach that the mucosal surface is the conjunctiva of the eye, one of ordinary skill in the art would have a reasonable expectation of success to administer levosimendan or OR-1896 by through the conjunctiva because levosimendan eye drops are known in the art. For example, Yan teaches levosimendan eye drops:
levosimendan solution formulations of the present invention can be prepared into different preparation forms, such as injection, injection freeze-dry powder, soft capsules, ointments, eye drops, oral liquid and so on.
Yan, Translation, Specification, paragraph 0015.
Due to the close structural and functional relationship between levosimendan and OR-1896 as demonstrated by Segreti, one of ordinary skill in the art would have no difficulty in substituting OR-1896 for levosimendan in a transmucosal composition such as eye drops.
Therefore, claim 1 was prima facie obvious at the time of filing.
Claim 2 recites:
A method according to claim 1, comprising administering to the eye of the patient in need thereof an effective amount of an eye drop composition comprising (R)-N- [4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]acetamide (I) as an active ingredient.
One of ordinary skill in the art would have a reasonable expectation of success to administer an effective amount of an eye drop comprising OR-1896 to a patient because it is commonly known to administer an effective amount of levosimendan by a transmucosal route, including by using eye drops, and OR-1896 is the active metabolite of levosimendan with the same therapeutic activity. For example, see the teachings of Segreti, Kurkela, and Yan above.
Therefore, claim 2 was prima facie obvious at the time of filing.
Given the above teachings, the invention as a whole was prima facie obvious at the time of filing.
Conclusion
No claim is found to be allowable.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/HEATHER DAHLIN/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629