The previous Final Office Action is withdrawn.
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 .
The Examiner previously noted claim 31 would be allowable if rewritten to incorporate all the limitations of claim 1, which was mistakenly noted. Thus, the previous claim amendments have not been entered and the instant office action is based on the claims received on February 3, 2025 and the Final Office Action mailed May 19, 2025. Hence, this is a 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
Claim 26 is objected to because of the following informalities: a period is missing at the end of the claim. Appropriate correction is required.
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.
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(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived 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 Patani, et al. (Chem. Rev., 96, 1996, pp. 3147-3176).
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.
A hydrogen versus fluorine is a common bioisostere replacement. Patani teaches that F is a classical bioisostere of H, see page 3149. Patani also teaches, “The ability of a group of bioisosteres to elicit similar biological activity has been attributed to common physicochemical properties,” see page 3148, first full paragraph. Patani further teaches that “[b]ioisosterism represents one approach used by the medicinal chemist for the rational modification of lead compounds into safer and more clinical effective agents. The concept of bioisosterism is often considered to be qualitative and intuitive,” see page 3147. Patani acknowledges that “[t]he substitution of hydrogen by fluorine is one of the more commonly employed monovalent isosteric replacements,” see page 3149. Patani goes on to teach that “the ability of fluorine to replace hydrogen is an effective method of exploring the affinity of an agent to the target site (receptor or enzyme) by virtue of its greater electronegativity while other parameters such as steric size and lipophilicity are maintained,” see page 3150. The reference further states, “The pharmacological differences can be attributed to the influence of the electron-withdrawing effect that the fluorine substitution causes on interaction with either a biological receptor or enzyme, as well as its effect on the metabolic fate of the drug,” page 3149, right-hand column, fourth full paragraph.
One more halogen does not constitute a patentable advance. See Ex parte Dole, 119 USPQ 260; Ex parte Teter 105 USPQ 192.
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 et al. in view of Patani, et al.
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 Patani, et al. (Chem. Rev., 96, 1996, pp. 3147-3176).
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.
A hydrogen versus fluorine is a common bioisostere replacement. Patani teaches that F is a classical bioisostere of H, see page 3149. Patani also teaches, “The ability of a group of bioisosteres to elicit similar biological activity has been attributed to common physicochemical properties,” see page 3148, first full paragraph. Patani further teaches that “[b]ioisosterism represents one approach used by the medicinal chemist for the rational modification of lead compounds into safer and more clinical effective agents. The concept of bioisosterism is often considered to be qualitative and intuitive,” see page 3147. Patani acknowledges that “[t]he substitution of hydrogen by fluorine is one of the more commonly employed monovalent isosteric replacements,” see page 3149. Patani goes on to teach that “the ability of fluorine to replace hydrogen is an effective method of exploring the affinity of an agent to the target site (receptor or enzyme) by virtue of its greater electronegativity while other parameters such as steric size and lipophilicity are maintained,” see page 3150. The reference further states, “The pharmacological differences can be attributed to the influence of the electron-withdrawing effect that the fluorine substitution causes on interaction with either a biological receptor or enzyme, as well as its effect on the metabolic fate of the drug,” page 3149, right-hand column, fourth full paragraph.
One more halogen does not constitute a patentable advance. See Ex parte Dole, 119 USPQ 260; Ex parte Teter 105 USPQ 192.
Furthermore, the specific diastereomer or isomer may be synthesized or 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).
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 et al. in view of Patani, et al.
Applicant addresses both 103 rejections with the following: 1) a discussion of the Patani reference; 2) motivation for the replacement at the 2-position; 3) a discussion of the superior biological activity to that of UDCA; 4) Applicant notes the differences between compounds 6, 9, 10 and 10 versus UDCA and TUDCA, including the discussion of the stereochemistry differences and 5) comparative data for the claimed compounds.
This is not persuasive.
Applicant disagrees with the statement in Patani, which notes, “The substitution of hydrogen by fluorine is one of the more commonly employed monovalent isosteric replacements (Patani, page 3149).” Applicant further explains, “The point of the bioisosteric replacement strategy is that the bioisostere has similar physicochemical properties to the atom or group it replaces (i.e. similar steric properties, not similar chemical properties). While fluorine may be viewed as a bioisosteric equivalent to hydrogen, the motivation for such a replacement must be substantiated by empirical evidence demonstrating that the biological properties remain consistent post-substitution. For example, studies have shown that the replacement of hydrogen with fluorine can lead to significant alterations in biological activity, which may not always align with the anticipated outcomes based on the mere physicochemical similarity (Krautwald et al., 2016; submitted herewith in Appendix A). Therefore, one of ordinary skill in the art would understand that the decision to implement such a substitution of hydrogen with fluorine may have profound implications on the compound's pharmacodynamics and pharmacokinetics (Meanwell, 2011'; submitted herewith in Appendix B). Even Patani states:
Steric parameters for hydrogen and fluorine are similar... Thus, the difference in the electronic effects... is often the basis for the major differences in the pharmacological properties of agents where fluorine has been substituted for hydrogen. (Patani, page 3149; Emphasis Added)
In particular, the electronic effects of fluorine, primarily its high electronegativity (3.98 on the Pauling scale), introduces notable differences in the behavior of the substituted compounds. Fluorine's electronegativity imparts a stronger electron-withdrawing effect compared to hydrogen, which can significantly influence the electronic distribution within the molecule, thereby affecting its interaction with biological targets (Han & Zhang, 2020; Cavaliereet al., 2017; submitted herewith in Appendix C, and Appendix D, respectively).”
As Applicant noted, there are differences and similarities with the properties and biological activities with a bioisosteric replacement. This is also the case with the replacement of any atom or group on a molecule, which is the reason for structure-activity relationship studies. For example, even the replacement of a methyl group with an ethyl group, which is larger, affects the steric interactions of the binding molecule. However, homologues are considered equivalent and obvious, see In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). The replacement of hydrogen with a fluorine is one of the more commonly employed monovalent isosteric replacements used by medicinal chemists due to the similarities and differences in properties and biological activities.
Applicant has cited several references to provide support for the non-obviousness of a hydrogen replacement with a fluorine atom. However, none of the compounds in the references provided are similar in structure. As evidentiary support, the Examiner is providing a reference, Yang et al. (Bioorganic and Medicinal Chemistry Letters, 2014, 14(4), 1222-1227), that shows the substitution of a fluorine atom for a hydrogen atom at the 2-position in similar compounds, which fall outside the scope of the present claims, see compounds 29 and 34 and compounds 32 and 33 for comparison. Table 1 provides percent of NO inhibition and percent of cell viability data at 40 uM for the non-fluorinated (at position 2) steroid compounds 29 (69.6% and 76.6%, respectively) and 32 (44.5% and 76.6%, respectively) compared to the fluorinated compounds 34 (92.7% and 55.9%, respectively) and 33 (63.8% and 86.8%, respectively). Thus, comparing compound 29 to compound 34, and compound 32 and compound 33, the fluorinated compounds 33 and 34 have higher % of inhibition. The percent of cell viability is higher for compound 29 (non-fluorinated) versus 34 and lower for the nonfluorinated compound 32 versus 33. Thus, to increase NO percent of inhibition, fluorinating at the 2-position of the steroid core gives a higher percentage.
Applicant states, “Applicants submit that a person of ordinary skill in the art would not have any reasonable expectation of success from the teaching of Patani, and from the references submitted herewith (Krautwald et al., 2016, Meanwell, 2011; Meanwell, 2021, Han & Zhang, 2020; and Cavaliereet al., 2017), that a derivative in which a hydrogen atom of a parent compound is replaced by a fluorine atom would have a similar biological activity to that of the parent compound.”
However, this seems to contradict that the substitution of hydrogen by fluorine is one of the more commonly employed monovalent isosteric replacements. When chemical compounds have "very close" structural similarities and similar utilities, a prima facie case of obviousness may be made, In re Grabiak (CAFC 1985) 769 F2d 729, 226 USPQ 870. Similarly, obviousness can be based on the concept of "isosterism", viz., the substitution in a parent compound of one atom or a group of atoms for another atom or group of atoms having a similar electronic and steric configuration. Ex parte Engelheardt (POBA 1980) 208 USPQ 243; In re Merck &Co. Inc. (CAFC 1986) 800 F2d 1091, 231 USPQ 375.
Applicant further argues, “[E]ven if a person of ordinary skill in the art were to consider replacement of one or more hydrogen atoms with fluorine, there is no teaching or description in Low and/or Patani which would motivate a person of skill in the art to select the 2-position as a suitable site for replacement of H with F. There are 22 hydrogen atoms at 15 sites on the UDCA skeleton, any of which could potentially be replaced with fluorine, and nothing in Low and/or Patani teaches or suggests the particular selection which has been made of one or two fluorine atoms replacing one or two hydrogen atoms at the 2-position of the ring system.
It is beyond question that fluorination has been used to develop important drugs. Uracil became 5-Fluorouracil, 5-FU, for treating cancer, which was developed in the 1950s, as was 9-Fluorohydrocortisone as an anti-inflammatory and for a range of other uses. Familiar names like Lipitor®, Risperdal®, Advair®, Cipro® and Prevacid® have been enormous successes. Prozac® (Fluoxetine), Citalopram® (Celexa) and indeed, most SSRI antidepressants, have F present. The F helps these drugs get into the brain and help improve pharmacokinetic properties. The present compounds are disclosed to treat Parkinson’s Disease, Alzheimer’s Disease and dementia with Lewy bodies, which may require that the drug is able to permeate the blood brain barrier, which the addition of fluorine on the drug may increase the likelihood. The claims are obvious because it would have been obvious to try fluorine substitution on the molecule with a reasonable expectation of success.
Applicant further states, “The fluorinated compounds of the presently claimed invention do not have similar biological activity to UDCA; they actually have superior biological activity to that of UDCA. It would certainly not have been expected from the teaching or description of Low and/or Patani that the replacement of H with F at the 2-position would not merely lead to compounds which elicit similar biological activity to that of UDCA; rather the compounds of the presently claimed invention actually give rise to compounds with superior activity. For example, the superior activity is demonstrated in the biological examples, as compounds of the presently claimed invention were able to restore mitochondrial membrane potential and cellular ATP levels in fibroblasts from Parkinson's disease patients to control levels (see Tables 1 to 4, on pages 85-87 of the as-filed Specification). Further, the compounds of formulas (IA), (IB) or (IC) of claim 3, are non-obvious for at least the reasons discussed above, and because the compounds have different stereochemistry from UDCA and TUDCA at the 3- and/or 7-positions of the bile acid ring system. Specific example compounds of the presently claimed invention, which have different stereochemistry from UDCA and TUDCA, are Compounds 1-5, 7, 8 and 10-31. Compounds 1, 5 and 8 are compounds of Formula (IB) of claim 3; Compounds 2 and 3 are compounds of Formula (IC) of claim 3; and Compounds 4, 7 and 10-31 are compounds of Formula (IA). Applicants submit that all of these compounds are non- obvious over the combination of Low and Patani both because they are fluorinated at the 2-position and for the additional reason that they have different stereochemistry from UDCA and TUDCA at the 3- and/or 7-positions of the bile acid ring system.”
Applicant points to Tables 1-4 but does not provide the exact comparison. The Examiner has not found a direct comparison that is commensurate in scope with the claimed genus in claim 1 or claim 3 that shows the presently claimed compounds actually have superior biological activity to that of UDCA. Furthermore, a difference in stereochemistry is not sufficient to deem a compound as non-obvious. Moreover, claim 1 embraces the different stereochemistry at C-2, C-3 and C-7. Lastly, claims 32 and 35 were determined to be allowable based on the claimed species.
Applicant further explains, “On page 6, the Office Action asserts that the specific isomer would be isolated because the alpha versus beta stereocenter have different binding affinities, and therefore the stereoisomers are obvious. However, it is not clear from the Office Action or the combination of Low and Patani how the specific diastereomer or isomer would be isolated. As can be seen from the corresponding PCT specification at pages 16 to 27 and from Examples 1 to 3 (i.e., see International Application No. PCT/GB2019/053665), specific experimental methods had to be devised in order to prepare compounds having the required stereochemistry. The combination of Low and Patani have no teaching or suggestion to one of ordinary skill in the art to simply isolate the required isomer to prepare the claimed compounds. One of ordinary skill in the art would understand that neither fluorination chemistry nor the chemistry of bile acids is simple, and as demonstrated in Applicant's Specification, the inventors had to develop suitable experimental methods to enable them to synthesize the presently claimed compounds. The data presented in Figures 1 to 3 and Table 5, and described on pages 85-89 of the Specification show that Compound 7 has superior activity to UDCA in a number of assays carried out on fibroblasts, or in neurons from sPD patients, or on mouse brain homogenate. Compound 7 has different stereochemistry from UDCA so this improved activity would not have been expected.”
As previously noted, compound 7 in claim 32 is allowable. The Examiner stated the different isomers may be isolated since one isomer has different biological properties compared to the other isomer. The rejection has been amended to may be synthesized or isolated to obtain the other isomer. One of ordinary skill in the art, e.g. an organic chemist, is able to synthesize or isolate, different stereoisomers which is a common laboratory practice. Furthermore, a specific diastereomer or isomer may be synthesized or 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).
Applicant further contends, “See paragraph [0668] of U.S. Publication No. 2022/0073557, "The data clearly show that treatment with compounds 2, 7 and 8 have a more beneficial restoration of cellular ATP levels than UDCA treatment.
The results presented in Table 6 and described on pages 89-90 of the Specification demonstrate that Compounds 2, 7 and 8 all have a more beneficial restoration of cellular ATP levels than UDCA treatment in fibroblasts from patients with Alzheimer's disease. Compounds 2 and 8 are particularly effective in this assay, increasing ATP levels dramatically. This would certainly not have been expected by a skilled person as Compounds 2 and 8 have the same stereochemistry as CDCA and would not have been expected to be active at all. "
Compounds 2, 7, and UDCA are provided below for comparison with Table 6 of the US 20220073557 publication, paragraph [0667-0668].
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Since there is more than one difference at C-2, C-3 and/or C-7, the Examiner is not able to determine a trend that may be commensurate in scope with claims 1 or 3. However, based on this assay, compounds 2, 7 and 8 have unexpected results over UDCA.
Moreover, MPEP 716.02(D) states, “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of non-obviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980). The non-obviousness of a broader claimed range can be supported by evidence based on unexpected results from testing a narrower range if one of ordinary skill in the art would be able to determine a trend in the exemplified data which would allow the artisan to reasonably extend the probative value thereof. In re Kollman, 595 F.2d 48, 201 USPQ 193 (CCPA 1979). The disclosure and declaration provide results for three compounds which are embraced by the very large genus of formula (I-A) , which are not commensurate in scope.
Therefore, the rejection is maintained.
Claim 31 is rejected under AIA 35 U.S.C. 103(a) as being unpatentable over Ferrari et al. (US 9206220) in view of Patani, et al. (Chem. Rev., 96, 1996, pp. 3147-3176).
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. Patani teaches that F is a classical bioisostere of H, see page 3149. Patani also teaches, “The ability of a group of bioisosteres to elicit similar biological activity has been attributed to common physicochemical properties,” see page 3148, first full paragraph. Patani further teaches that “[b]ioisosterism represents one approach used by the medicinal chemist for the rational modification of lead compounds into safer and more clinical effective agents. The concept of bioisosterism is often considered to be qualitative and intuitive,” see page 3147. Patani acknowledges that “[t]he substitution of hydrogen by fluorine is one of the more commonly employed monovalent isosteric replacements,” see page 3149. Patani goes on to teach that “the ability of fluorine to replace hydrogen is an effective method of exploring the affinity of an agent to the target site (receptor or enzyme) by virtue of its greater electronegativity while other parameters such as steric size and lipophilicity are maintained,” see page 3150. The reference further states, “The pharmacological differences can be attributed to the influence of the electron-withdrawing effect that the fluorine substitution causes on interaction with either a biological receptor or enzyme, as well as its effect on the metabolic fate of the drug,” page 3149, right-hand column, fourth full paragraph.
One more halogen does not constitute a patentable advance. See Ex parte Dole, 119 USPQ 260; Ex parte Teter 105 USPQ 192.
“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 Patani, et al.
Conclusion
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/SUSANNA MOORE/Primary Examiner, Art Unit 1624