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 .
This is Non-Final Office Action.
Claims 1, 3-6, 8, 10, 13, 16, 18, 21, 24, 26-28 and 30-38 are pending and under consideration.
Claim Objections
The objection to claim 26 because a period was missing is withdrawn based on the amendments.
Claims 32, 35 and 37 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim Rejections - 35 USC § 112
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 16 and 31 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Regarding claim 16, the R14 variable is not found in claim 1 in the definition of R3. Moreover, R14 is not defined as a H and R12 is not defined as S(O)2OH. Furthermore, the claim states, “both R15 moieties” but there is only one R15 in claim 16. Thus, said claim is vague and indefinite.
With regards to claim 31, the definition of R3 in the 4th line and the first line under formula (II) in subsection A are not the same. Therefore, said claim is indefinite.
Also in claim 31, subsection O is indefinite of the term intermediate of (M) and (N).
The following is a quotation of the fourth paragraph of 35 U.S.C. 112:
Subject to the [fifth paragraph of 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 10 is rejected under 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. Regarding claim 10, the R16 substituent substituted on the 5- or 6-membered heterocyclic ring formed by R12 and R13 in the definition of R3 does not further limit claim 1.
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(s) complies with the statutory requirements.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 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).
Claims 1, 3-6, 8, 21, 24, 26-28, 30, 33 and 38 are rejected under AIA 35 U.S.C. 103(a) as being unpatentable over Low et al. (WO 2014036379) in view of Silverman (The Organic Chemistry of Drug Design and Drug Action, Academic Press. Inc. 1992, 19-23), Kim et al. (Korean J. Chem. Eng., 2008, 25(11), 171-175), and Roda et al. (Gastroenterology, 1995, 108, 1204-1214).
The present application claims compounds of formula (I), wherein R1= H or F, R2= H or F, 3-OH= alpha and beta, 7-OH= alpha and beta, Y= CH2CH2 and R3= C(O)OH and wherein one or both of R1 or R2 is F (see compounds 6 and 9 below):
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The reference teaches the following species, wherein R1= H, R2= H, 3-OH= alpha, 7-OH= beta, Y= CH2CH2 and R3= C(O)OH:
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see page 1, line 27, as a treatment for Parkinson’s Disease or Alzheimer’s Disease, see page 5, lines 31-32, two of the same utilities currently claimed. The compositions are taught on pages 8-9.
The differences between the cited compound above and the claimed compounds are: 1) the substitutions at the 2-position of the steroid core, H versus Applicant’s one or two fluourine atoms; and 2) the stereochemistry at the 3-position, beta versus Applicant’s alpha, see claim 4.
Kim et al. teaches UDCA has low bioavailability due to low solubility, see page 171, right hand column, first full paragraph.
Roda et al. teaches, “There is a need for new, more active UDCA analogues
that are more stable during intestinal bacterial metabolism but, at the same time, have physicochemical and biological properties that facilitate accumulation in the enterohepatic circulation by displacement of endogenous bile acid,” see page 1205, left-hand column, first full paragraph. The reference teaches the introduction of a fluorine atom at the 6-position of UDCA to prevent intestinal bacterial metabolism, but also teaches that 6-FUDCA is more hydrophilic than it’s parent analogue, see page 1205, right-hand column, first full paragraph. Thus, the introduction of fluorine atom on the steroid core increased the hydrophilicity of the molecule.
A hydrogen versus fluorine is a common bioisostere replacement. Silverman teaches that “Bioisosterism is a lead modification approach that has been shown to be useful to attenuate toxicity or to modify the activity of a lead, and it may have a significant role in the alteration of metabolism of a lead.” See page 19. Silverman further states, “Bioisosteres are substituents or groups that have chemical or physical similarities, and which produce broadly similar biological properties,” see page 19. Silverman identifies the following atoms as nonclassical isosteres: H and F, see page 20, Table 2.3, bottom of page. Therefore, the monovalent H atom is a nonclassical isostere of the monovalent F.
There would have been a reasonable expectation of success, since Silverman discloses that bioisosteres are substituents or groups that have chemical or physical similarities, and which produce broadly similar biological properties. Further, a prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 373, 203 USP 245, 254 (COCPA 1979). In re Papesch, 315 F.2d 381, 137 USPO 43 (CCPA 1963) and In re Dillon, 919 F.2d 688, 16 USPO2d 1997 (Fed. Cir, 1990). See also MPEP § 2144.09.
Furthermore, the specific diastereomer or isomer would be isolated because the alpha versus beta stereocenter have different binding infinities since proteins in the body are also chiral, see In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious).
“Structural similarity, alone, may be sufficient to give rise to an expectation that compounds similar in structure will have similar properties.” In re Payne, 606 F.2d 303, 313 (CCPA 1979).
Therefore, the instant invention is prima facie obvious from the teachings of the prior arts. One of ordinary skill in the art would have known to replace H with F and claim bioisosteric equivalents of prior art compounds at the time the invention was made. The motivation is from knowing that bioisosteric equivalents would have similar biological properties, and that H and F are art recognized equivalents.
Therefore, it would be obvious to make the elected species based on the teachings of Low in view of Silverman, Kim and Roda.
Claims 1, 3-6, 8, 10, 13, 16, 18, 21, 24, 26-27, 30, 34, 36 and 38 are rejected under AIA 35 U.S.C. 103(a) as being unpatentable over Low et al. (WO 2014036379) in view of Silverman (The Organic Chemistry of Drug Design and Drug Action, Academic Press. Inc. 1992, 19-23), Kim et al. (Korean J. Chem. Eng., 2008, 25(11), 171-175), and Roda et al. (Gastroenterology, 1995, 108, 1204-1214).
The present application claims compounds of formula (I), wherein R1= H or F, R2= H or F, 3-OH= alpha and beta, 7-OH= alpha and beta, Y= CH2CH2 and R3= C(O)N(H or methyl)CH2CH2S(O)2OH a and wherein one or both of R1 or R2 is F (see compounds 10 and 19 below):
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The reference teaches the following species, wherein R1= H, R2= H, 3-OH= alpha, 7-OH= beta, Y= CH2CH2 and R3= C(O)OH:
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see page 1, line 27, as a treatment for Parkinson’s Disease or Alzheimer’s Disease, see page 5, lines 31-32, two of the same utilities currently claimed. The compositions are taught on pages 8-9.
The differences between the cited compound above and the claimed compounds are: 1) the substitutions at the 2-position of the steroid core, H versus Applicant’s one or two fluourine atoms; 2) the stereochemistry at the 3-position, beta versus Applicant’s alpha, see claim 4; and 3) H versus Applicant’s methyl, see claim 36.
Kim et al. teaches UDCA has low bioavailability due to low solubility, see page 171, right hand column, first full paragraph.
Roda et al. teaches, “There is a need for new, more active UDCA analogues
that are more stable during intestinal bacterial metabolism but, at the same time, have physicochemical and biological properties that facilitate accumulation in the enterohepatic circulation by displacement of endogenous bile acid,” see page 1205, left-hand column, first full paragraph. The reference teaches the introduction of a fluorine atom at the 6-position of UDCA to prevent intestinal bacterial metabolism, but also teaches that 6-FUDCA is more hydrophilic than it’s parent analogue, see page 1205, right-hand column, first full paragraph. Thus, the introduction of fluorine atom on the steroid core increased the hydrophilicity of the molecule.
A hydrogen versus fluorine is a common bioisostere replacement. Silverman teaches that “Bioisosterism is a lead modification approach that has been shown to be useful to attenuate toxicity or to modify the activity of a lead, and it may have a significant role in the alteration of metabolism of a lead.” See page 19. Silverman further states, “Bioisosteres are substituents or groups that have chemical or physical similarities, and which produce broadly similar biological properties,” see page 19. Silverman identifies the following atoms as nonclassical isosteres: H and F, see page 20, Table 2.3, bottom of page. Therefore, the monovalent H atom is a nonclassical isostere of the monovalent F.
There would have been a reasonable expectation of success, since Silverman discloses that bioisosteres are substituents or groups that have chemical or physical similarities, and which produce broadly similar biological properties. Further, a prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 373, 203 USP 245, 254 (COCPA 1979). In re Papesch, 315 F.2d 381, 137 USPO 43 (CCPA 1963) and In re Dillon, 919 F.2d 688, 16 USPO2d 1997 (Fed. Cir, 1990). See also MPEP § 2144.09.
Furthermore, the specific diastereomer or isomer would be isolated because the alpha versus beta stereocenter have different binding infinities since proteins in the body are also chiral, see In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious).
“Structural similarity, alone, may be sufficient to give rise to an expectation that compounds similar in structure will have similar properties.” In re Payne, 606 F.2d 303, 313 (CCPA 1979).
A hydrogen is a homologue of methyl with regards to the substitution on the nitrogen of the R3 variable, H versus Applicant’s methyl, and this substitution is considered equivalent. The MPEP 2144.09 states “Compounds which are… homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).
“Structural similarity, alone, may be sufficient to give rise to an expectation that compounds similar in structure will have similar properties.” In re Payne, 606 F.2d 303, 313 (CCPA 1979).
Therefore, the instant invention is prima facie obvious from the teachings of the prior arts. One of ordinary skill in the art would have known to replace H with F and claim bioisosteric equivalents of prior art compounds at the time the invention was made. The motivation is from knowing that bioisosteric equivalents would have similar biological properties, and that H and F are art recognized equivalents.
Therefore, it would be obvious to make the elected species based on the teachings of Low in view of Silverman, Kim and Roda.
Claim 31 is rejected under AIA 35 U.S.C. 103(a) as being unpatentable over Ferrari et al. (US 9206220) in view of Silverman (The Organic Chemistry of Drug Design and Drug Action, Academic Press. Inc. 1992, 19-23).
The present application claims a process for the preparation of a compound of formula (I), wherein R1= H or F, R2= H or F, 3-OH= alpha and beta, 7-OH= alpha and beta, Y= CH2CH2 and R3= C(O)OH and wherein one or both of R1 or R2 is F (see compounds 6 and 9 below) by hydrolyzing a compound of formula (I) (see step F), wherein R1= H or F, R2= H or F, 3-OH= alpha and beta, 7-OH= alpha and beta, Y= CH2CH2 and R3= C(O)Oalkyl:
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The reference teaches a process for the preparation of a compound of formula (I), wherein R1= H, R2= H, 3-OH= alpha, 7-OH= beta, Y= CH2CH2 and R3= C(O)OH by hydrolyzing a compound of formula (I), wherein wherein R1= H or F, R2= H or F, 3-OH= alpha and beta, 7-OH= alpha and beta, Y= CH2CH2 and R3= C(O)OCH3:
:
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, see columns 7-8 of the ‘220 patent.
The difference between the cited compound above and the claimed compounds is the substitutions at the 2-position of the steroid core, H versus Applicant’s one or two fluourine atoms.
A hydrogen versus fluorine is a common bioisostere replacement. A hydrogen versus fluorine is a common bioisostere replacement. Silverman teaches that “Bioisosterism is a lead modification approach that has been shown to be useful to attenuate toxicity or to modify the activity of a lead, and it may have a significant role in the alteration of metabolism of a lead.” See page 19. Silverman further states, “Bioisosteres are substituents or groups that have chemical or physical similarities, and which produce broadly similar biological properties,” see page 19. Silverman identifies the following atoms as nonclassical isosteres: H and F, see page 20, Table 2.3, bottom of page. Therefore, the monovalent H atom is a nonclassical isostere of the monovalent F.
“Structural similarity, alone, may be sufficient to give rise to an expectation that compounds similar in structure will have similar properties.” In re Payne, 606 F.2d 303, 313 (CCPA 1979).
The reference further teaches the reduction of a compound of formula (XIIB) to a compound of formula (IB) or (ID), see step C:
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, see columns 5-6.
Therefore, the instant invention is prima facie obvious from the teachings of the prior arts. One of ordinary skill in the art would have known to replace H with F and claim bioisosteric equivalents of prior art compounds at the time the invention was made. The motivation is from knowing that bioisosteric equivalents would have similar biological properties, and that H and F are art recognized equivalents.
Therefore, it would be obvious to make the elected species based on the teachings of Ferrari et al. in view of Silverman et al.
Conclusion
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/SUSANNA MOORE/Primary Examiner, Art Unit 1624
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