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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on December 3, 2025, has been entered.
Detailed Action
This office action is a response to applicant’s communication submitted December 3, 2025, wherein the rejections of record in the previous action are traversed. This application is a continuation of US application 16/604867, now abandoned, filed October 11, 2019, which is a national stage application of PCT/US2018/027462, filed April 13, 2018, which claims benefit of provisional applications 62/489546, filed April 25, 2017, 62/488287, filed April 21, 2017, and 62/485260, filed April 13, 2017.
Claims 1 and 3-9 are pending in this application.
Claims 3-9 are withdrawn from consideration for being drawn to non-elected subject matter.
Claim 1 as amended is examined on the merits herein.
The following rejections of record in the previous action are maintained:
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.
Claim 1 is are rejected under 35 U.S.C. 103 as being unpatentable over Gin et al. (PCT international publication WO2015/184451, reference included with PTO-1449 submitted March 22, 2023) in view of Rodriguez-Diaz et al. (Reference included with PTO-1449) in view of Tan et al. (PCT international publication WO2017/106836, reference included with PTO-1449 submitted March 22, 2023) in view of Chea et al. (Non-patent literature reference C10 cited in 3/22/2023 PTO-1449) in view of Adams et al. (Non-patent literature reference C3 cited in 3/22/2023 PTO-1449) In view of Squarcia et al. (Reference of record in previous action) in view of Liu et al. (Reference of record in previous action)
Independent claim 1 is directed to a method of synthesizing a particular saponin compound, comprising purifying an aglycone compound (Quillaic acid) from Quillaja bark extract, and then carrying out a sequence of six chemical transformations on the compound so as to arrive at a specific product:
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Gin et al. discloses a minimal saponin analog compound having a structure:
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Wherein X can be an –NH-acyl group and Rn represents a hydrogen or saccharide. (p. 2 paragraph 5) In a specific embodiment the compound has the structure:
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Which when W is –C(=O)H and V is –OH, is similar to the compound produced by the process of claim 1, except that it contains a 6-aminohexanoic acid amide in place of a 1,12-dodecanedioic acid amide. (p. 4 paragraph 13) This compound can be made by a process starting from Quillaic acid (10):
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Which is subjected to TES-protection, coupling with a compound (12):
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Followed by reduction of the azide to an amine, coupling with a protected 6-aminohexanoic acid, and deprotection to form the final product. (pp. 26-28 paragraph 80, pp. 54-57 paragraphs 165-169) This process comprises the same steps recited in present claim 1 with the exception of the first purification step.
However, Rodriguez-Diaz et al. discloses that quillaic acid can be purified from a semi-purified Q. saponaria extract referred to as 100Q. (p. 719 under the headings “General procedures” and “isolation and characterization of quillaic acid (1)”) This purified compound is then used to synthesize a variety of derivatives which are tested for anti-inflammatory activity. (p. 721 figure 1, also the paragraph labeled “topical anti-inflammatory activity”) Therefore it would have been obvious to one of ordinary skill in the art at the time of the invention to perform a purification of quillaic acid from semi-purified extract 100Q or a similar semi-purified extract of Q. saponaria, and then to use the purified quillaic acid as a starting material in a synthesis according to Gin et al. One of ordinary skill in the art would have seen the disclosure of Gin et al. as suggesting using any existing prior art source of quillaic acid as a starting material because this reference uses this compound in its synthesis. Furthermore the fact that Rodriquez-Diaz et al. uses this compound as the starting material for synthesis for further biologically active compounds provides a reasonable expectation of success in using it as a starting material in the synthesis described by Gin et al.
The claimed invention also differs from that of Gin et al. in that the acid coupled to the amine group is 1,12-dodecanedioic acid rather than 6-aminohexanoic acid. However Tan et al. discloses similar saponin derivative compounds. (p. 2 paragraph 6) Specific embodiments of these compounds include those wherein the saccharide esterified at the carboxyl group of quillaic acid is the same dodecanedioic acid amidated trisaccharide appearing in the compound synthesized in the process of claim 1. (pp. 46-48 paragraph 159, especially compound (6)) This structure furthermore includes embodiments wherein G is hydrogen, which would correspond to the hydroxyl compounds synthesized in the presently claimed process. (p. 40 paragraph 137) When the dodecanedioic acid amide is used, it is formed by a step wherein the benzyl-protected carboxylic acid is coupled to the aminosugar moiety and then deprotected by reduction. (p. 94 paragraph 282., p. 96 paragraph 284, and reaction drawings immediately preceding these paragraphs)
It would have been obvious to one of ordinary skill in the art at the time of the invention to make a compound corresponding to the compound produced by Gin et al. wherein the 6-aminohexanoyl amide is replaced by a 12-carboxydecanoyl amide as described by Tan et al. One of ordinary skill in the art would have found it to be obvious to make such compounds because they fall within the generic disclosure of Tan et al., wherein G is hydrogen and Z is the dodecanedioic acid amide trisaccharide. Furthermore one of ordinary skill in the art would have found it to be obvious to apply the synthetic steps described by Gin et al. to the construction of these compounds as Gin et al. describes this synthetic scheme as being useful for producing a closely related compound.
With respect to the further limitation requiring that the compound C-1 be synthesized by the reaction steps:
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, Gin et al. does not specifically describe a method of making C-1 that requires these steps. However, Gin et al. does disclose this compound (compound 12 referenced in p. 59 paragraph 172) and describes it with reference to the reference Chea et al. (p. 44 paragraph 145) Chea et al. further discloses this trisaccharide as being made by a process (scheme 2 on p. 13451) involving a compound 20 which is described as being previously prepared with reference to the publication of Adams et al. (p. 13452, left column first paragraph, also citation 19 on p. 13456) Adams et al. discloses this compound as being prepared by a process including the steps:
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. (p. 1941 scheme 1) Squarcia et al. further discloses making a compound equivalent to compound 4 of Adams et al. by a process comprising reacting compound 3a:
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or 3b:
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by the process
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wherein condition a includes BzCl and pyridine and b includes sodium azide. (p. 4654 schemes 1 and 2) Therefore it would have been obvious to one of ordinary skill in the art, in carrying out the synthetic strategy described by Gin, to make the trisaccharide compound 12 by the steps described by Squarcia et al. One of ordinary skill in the art would have found this to be obvious because Gin et al. specifically suggests using synthetic routes of this type through reference to Chea, and then reference to Adams by the disclosure of Chea. While the synthetic steps described in Squarcia’s disclosure differ from the ones recited in present claim 1 by the use of MsCl followed by sodium azide to displace the hydroxide with azide, Liu et al. discloses a method of making a glucocorticoid saccharide conjugate including the synthetic step:
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, wherein condition C is DPPA, DIAD, PPh3 and THF. (p. 930 scheme 1) It would have been obvious to one of ordinary skill in the art at the time of the invention to use the synthetic reaction step described by Liu et al. in place of the mesyl chloride and sodium azide steps described by Adams and Squarcia et al. One of ordinary skill in the art would have substitutes one of these reaction conditions for the other because both reactions are seen to produce the same result, namely replacement of a hydroxyl group with an azide group.
For these reasons the invention taken as a whole is prima facie obvious.
Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over Gin et al. ‘451 (PCT international publication WO2015/184451, reference included with PTO-1449 submitted March 22, 2023) in view of Rodriguez-Diaz et al. (Reference of record in PTO-1449 submitted March 22, 2023) in view of Gin et al. ‘585. (US pre-grant publication 2015/0086585, cited in PTO-1449 submitted March 22, 2023) in view of Chea et al. (Non-patent literature reference C10 cited in 3/22/2023 PTO-1449) in view of Adams et al. (Non-patent literature reference C3 cited in 3/22/2023 PTO-1449) In view of Squarcia et al. (Reference of record in previous action) in view of Liu et al. (Reference of record in previous action)
Independent claim 1 is directed to a method of synthesizing a particular saponin compound, comprising purifying an aglycone compound (Quillaic acid) from Quillaja bark extract, and then carrying out a sequence of six chemical transformations on the compound so as to arrive at a specific product:
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Gin et al. ‘451 discloses a minimal saponin analog compound having a structure:
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Wherein X can be an –NH-acyl group and Rn represents a hydrogen or saccharide. (p. 2 paragraph 5) In a specific embodiment the compound has the structure:
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Which when W is –C(=O)H and V is –OH, is similar to the compound produced by the process of claim 1, except that it contains a 6-aminohexanoic acid amide in place of a 1,12-dodecanedioic acid amide. (p. 4 paragraph 13) This compound can be made by a process starting from Quillaic acid (10):
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Which is subjected to TES-protection, coupling with a compound (12):
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Followed by reduction of the azide to an amine, coupling with a protected 6-aminohexanoic acid, and deprotection to form the final product. (pp. 26-28 paragraph 80, pp. 54-57 paragraphs 165-169) This process comprises the same steps recited in present claim 1 with the exception of the first purification step.
However, Rodriguez-Diaz et al. discloses that quillaic acid can be purified from a semi-purified Q. saponaria extract referred to as 100Q. (p. 719 under the headings “General procedures” and “isolation and characterization of quillaic acid (1)”) This purified compound is then used to synthesize a variety of derivatives which are tested for anti-inflammatory activity. (p. 721 figure 1, also the paragraph labeled “topical anti-inflammatory activity”) Therefore it would have been obvious to one of ordinary skill in the art at the time of the invention to perform a purification of quillaic acid from semi-purified extract 100Q or a similar semi-purified extract of Q. saponaria, and then to use the purified quillaic acid as a starting material in a synthesis according to Gin et al. ‘451. One of ordinary skill in the art would have seen the disclosure of Gin et al. as suggesting using any existing prior art source of quillaic acid as a starting material because this reference uses this compound in its synthesis. Furthermore the fact that Rodriquez-Diaz et al. uses this compound as the starting material for synthesis for further biologically active compounds provides a reasonable expectation of success in using it as a starting material in the synthesis described by Gin et al. ‘451.
The claimed invention also differs from that of Gin et al. ‘451 in that the acid coupled to the amine group is 1,12-dodecanedioic acid rather than 6-aminohexanoic acid. However Gin et al. ‘585 discloses quillaja saponins derivatives of a similar structure. (p. 1 paragraph 8 – p. 2 paragraph 31) Furthermore derivatives are disclosed having no saccharide group at position C3, corresponding to the free hydroxyl continuing compounds described by Gin et al. ‘451 and instant claim 1. (p. 20 paragraph 234, p. 25 compound I-14) Furthermore Gin et al. ‘585 describes embodiments wherein the amide group on the aminosugar moiety is an alkylenedioic acid amide having 3-15 carbons, which encompasses the dodecanedioic acid amide of the instant claims. (p. 18 paragraph 217)
It would have been obvious to one of ordinary skill in the art at the time of the invention to make a compound corresponding to the compound produced by Gin et al. ‘451 wherein the 6-aminohexanoyl amide is replaced by a 12-carboxydecanoyl amide as described by Gin et al. ‘585. One of ordinary skill in the art would have found it to be obvious to make such compounds because they fall within the generic disclosure of Gin et al. 585, wherein G is hydrogen and Z is the dodecanedioic acid amide trisaccharide. Furthermore one of ordinary skill in the art would have found it to be obvious to apply the synthetic steps described by Gin et al. ‘451 to the construction of these compounds as Gin et al. ‘451 describes this synthetic scheme as being useful for producing a closely related compound.
With respect to the newly introduced limitation requiring that the compound C-1 be synthesized by the reaction steps:
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, Gin et al. does not specifically describe a method of making C-1 that requires these steps. However, Gin et al. does disclose this compound (compound 12 referenced in p. 59 paragraph 172) and describes it with reference to the reference Chea et al. (p. 44 paragraph 145) Chea et al. further discloses this trisaccharide as being made by a process (scheme 2 on p. 13451) involving a compound 20 which is described as being previously prepared with reference to the publication of Adams et al. (p. 13452, left column first paragraph, also citation 19 on p. 13456) Adams et al. discloses this compound as being prepared by a process including the steps:
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. (p. 1941 scheme 1) Squarcia et al. further discloses making a compound equivalent to compound 4 of Adams et al. by a process comprising benzoylating compound 3a:
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or 3b:
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by the process
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wherein condition a includes BzCl and pyridine and b includes sodium azide. (p. 4654 schemes 1 and 2) Therefore it would have been obvious to one of ordinary skill in the art, in carrying out the synthetic strategy described by Gin, to make the trisaccharide compound 12 by the steps described by Squarcia et al. One of ordinary skill in the art would have found this to be obvious because Gin et al. specifically suggests using synthetic routes of this type through reference to Chea, and then reference to Adams by the disclosure of Chea. While the synthetic steps described in Squarcia’s disclosure differ from the ones recited in present claim 1 by the use of MsCl followed by sodium azide to displace the hydroxide with azide, Liu et al. discloses a method of making a glucocorticoid saccharide conjugate including the synthetic step:
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, wherein condition C is DPPA, DIAD, PPh3 and THF. (p. 930 scheme 1) It would have been obvious to one of ordinary skill in the art at the time of the invention to use the synthetic reaction step described by Liu et al. in place of the mesyl chloride and sodium azide steps described by Adams and Squarcia et al. One of ordinary skill in the art would have substitutes one of these reaction conditions for the other because both reactions are seen to produce the same result, namely replacement of a hydroxyl group with an azide group.
For these reasons the invention taken as a whole is prima facie obvious.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 1 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 20 of U.S. Patent No. 10906926 (Reference of record in previous action, herein referred to as ‘926) in view Gin et al. (PCT international publication WO2015/184451, ref Reference of record in previous action) in view of Rodriguez-Diaz et al. (Reference of record in previous action) in view of Chea et al. (Non-patent literature reference C10 cited in 3/22/2023 PTO-1449) in view of Adams et al. (Non-patent literature reference C3 cited in 3/22/2023 PTO-1449) In view of Squarcia et al. (Reference of record in previous action) in view of Liu et al. (Reference of record in previous action)
Claim 20 of ‘926 claims a method corresponding to steps e-g recited in present claim 1. While this method does not include steps a-d, as discussed previously under 35 USC 103, Gin et al. discloses a similar chemical synthesis that includes steps corresponding to b-d, Rodriquez-Diaz et al. discloses purification of quillaic acid corresponding to step a, and Chea et al. in view of Adams et al. in view of Squarcia et al. in view of Liu et al. suggests the newly introduced synthetic scheme for C-1. It would have been obvious to one of ordinary skill in the art to carry out these steps as described by Gin and Rodriguez-Diaz in order to obtain the starting material for the process of claim 20 of ‘926. The fact that this process requires this compound as a starting material would suggest to one of ordinary skill in the art to look to the art to determine how to obtain this starting material.
Claim 1 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 20 of U.S. Patent No. 10906926 (Reference of record in previous action, herein referred to as ‘926) in view Gin et al. (PCT international publication WO2015/184451, Reference of record in previous action) in view of Hickie et al. (Reference of record in previous action) in view of Chea et al. (Non-patent literature reference C10 cited in 3/22/2023 PTO-1449) in view of Adams et al. (Non-patent literature reference C3 cited in 3/22/2023 PTO-1449) In view of Squarcia et al. (Reference of record in previous action) in view of Liu et al. (Reference of record in previous action)
Claim 20 of ‘926 claims a method corresponding to steps e-g recited in present claim 1. While this method does not include steps a-d, as discussed previously under 35 USC 103, Gin et al. discloses a similar chemical synthesis that includes steps corresponding to b-d, Rodriquez-Diaz et al. discloses purification of quillaic acid corresponding to step a, and Chea et al. in view of Adams et al. in view of Squarcia et al. in view of Liu et al. suggests the newly introduced synthetic scheme for C-1. It would have been obvious to one of ordinary skill in the art to carry out these steps as described by Gin and Rodriguez-Diaz in order to obtain the starting material for the process of claim 20 of ‘926. The fact that this process requires this compound as a starting material would suggest to one of ordinary skill in the art to look to the art to determine how to obtain this starting material.
Response to Arguments
Applicant’s arguments, submitted December 3, 2025, with respect to the above grounds of rejection, have been fully considered and not found to be persuasive to remove the rejections. Applicant argues that one of ordinary skill in the art would not have found it to pe obvious to replace a sodium azide displacement as described by Adams with the reaction described by Liu et al. Specifically, Liu et al. discloses the displacement of a primary alcohol, which is expected to react more readily than the secondary alcohol described by Adams et al. and Squarcia et al. Additionally Applicant argues that the reagents used by Liu’s reaction are more expensive than those used by Adams and Squarcia, leading one of ordinary skill in the art to avoid them in favor of the less expensive alternative reaction scheme.
With respect to the first argument, this is based on the assertion that one of ordinary skill in the art would have regarded a secondary alcohol Sn2 displacement as requiring more forcing conditions than primary alcohols, and would therefore have regarded the sodium azide substitution reaction used by Adams and Squarcia as superior to the TPP/DIAD promoted approach described by Liu for use in displacing a secondary alcohol. Firstly, this argument relies upon the assertion that one of ordinary skill in the art would have expected that methanesulfonyl activation followed by sodium azide displacement is generally more suitable than TPP/DIAD for azide substitution of secondary alcohols. This fact is asserted with no particular evidence that this is in fact the position of the art on this particular synthetic reaction. Secondly, the examiner notes that the sodium azide displacement reaction described by the prior art is actually not particularly efficient. As described by Squarcia, the displacement of hydroxyl by azide consists of two steps, methanesulfonyl activation with MsCl, followed by treatment with sodium azide. For the relevant diastereomer (3b in scheme 1 of Squarcia) the yields of these steps are 60% for the first step and 50% for the second, leading to an overall yield of only 30% for converting a hydroxyl to an azide. By contrast Liu’s reaction conditions (see p. 931 left column second paragraph of Liu) result in displacement in one step with a yield of 85%. Therefore in view of the totality of the teachings of the art, one of ordinary skill in the art would have regarded the approach of Adams and Squarcia as fairly low yielding compared to the alternative TPP/DIAD promoted reaction, even allowing for the difficulty of displacement of a secondary alcohol. While a finding that the prior art teaches away form a particular combination would be evidence against obviousness, in the present case no such teaching has been located. In fact, looking to the state of the art, the examiner points to the disclosure of Scott et al. (Reference included with PTO-892) which is cited to shed light on the question of whether one of ordinary skill in the art would have found it to be obvious to perform Sn2 displacement of a secondary alcohol using the claimed conditions. In particular, Scott et al. discloses synthesis of a seven-membered cyclic secondary amine. (p. 1117 scheme 1) The authors of this reference attempted to synthesize this compound from the secondary alcohol 3. (See p. 1118 left column third paragraph) When activated as a mesylate this alcohol was still inert to Sn2 displacement by nitrogen nucleophiles. By contrast, Mitsunobu conditions using DIAD/TPP as activator and DPPA as the azide resulted in the desired reaction with typical yields of 95%. (p. 1118 left column last paragraph) Therefore the prior art does not in any way teach away from using this reaction for displacement of secondary alcohols, and one of ordinary skill in the art would actually expect much higher yields than those observed by Adams and Squarcia.
Regarding the alleged expense of Liu’s reagents, according to MPEP 2145(VII), “The fact that a "combination would not be made by businessmen for economic reasons" does not mean that a person of ordinary skill in the art would not make the combination because of some technological incompatibility.” Furthermore according to MPEP 2145(X)(D)(1), “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." Suggesting that a particular reaction could potentially be more expensive than the prior art does not overcome a finding of obviousness.
Additionally, Applicant further argues that the citation of seven different documents and the number of modifications necessary to adapt the primary reference Gin et al. to arrive at the claimed process demonstrates that such a modification is the result of innovation and complex inference rather than ordinary common sense and would not have been obvious to one thinking along conventional lines.
Firstly, according to MPEP 2145(V), “Reliance on a large number of references in a rejection does not, without more, weigh against the obviousness of the claimed invention.” Therefore the mere fact that seven different references are cited does not weight against obviousness without additional factors.
Secondly, of the seven cited references, some are cited merely to provide elements admittedly left undefined by the primary reference. For example, Gin et al. describes synthesis starting from a quillaic acid starting material but does not state how this starting material was obtained. In such a case, looking to another prior art reference (Rodriguez-Diaz) for a natural source of the prior art process’s starting material is not indicative of inference or innovation, but simply the common-sense effort necessarily implied by the use of this compound in the art. In the case of the steps involved in producing the intermediate C-1, while Gin does not explicitly spell out these steps, as discussed in the body of the rejections, Gin specifically describes compound C-1 as an intermediate and then cites Chea et al. as a method of making said intermediate. Chea et al. then, as discussed previously, cites Adams et al. to explain the synthesis of one of the starting materials in its synthetic scheme, and Adams et al. then cited Squarcia et al. to provide a synthesis of their own starting material 3. (See p. 1940 right column last paragraph of Adams, and also citation 25 of this reference) Therefore there is a chain of citations from Gin to Chea to Adams to Squarcia which is plainly spelled out in the literal teachings of the prior art and would lead one of ordinary skill in the art to use each of these references in turn as a source of the starting material for the next reference. Combining these references is therefore merely making up elements which are left undefined in the primary reference with the direct, obvious guidance of the authors of the prior art references specifically suggesting the combination of these references.
Looking at the claimed process as a whole, present claim 1 claims not a single chemical reaction but a complex synthetic scheme of nine separate steps. Given the length of the synthesis and the number of steps it is not surprising that they are not all disclosed together in one or two references. As shown in the rejections of record, most of the steps in the process of claim 1 are actually well-known predictable chemical reactions used in the prior art in the synthesis of similar molecules and very specifically suggested as being usable together in a single synthesis by the chain of citations in the prior art. The only modifications that do not directly fit this pattern are a) the adaptation of Gin’s synthesis to make a derivative wherein the amino group is amidated with 1,12-dodecanedioic acid rather than 6-aminohexanoic acid, and b) the use of a high-yielding Mitsunobu displacement in place of a low-yielding sodium azide displacement in the synthesis of intermediate C-1.
In the case of a), this is a matter of altering one step occurring late in a known synthesis to make a known product of very similar structure. Considering that the desired product was already known in the art, slightly altering one of the building blocks in Gin’s synthesis amounts to simple substitution of one known element for another to obtain predictable results according to MPEP 2143(I)(B). In the case of b), using the Mitsunobu reaction instead of methanesulfonyl chloride activation and sodium azide displacement amounts to using a known technique to improve a similar process, according to MPEP 2143(I)(C). Therefore none of the differences between Gin’s synthesis and the process of present claim 1 amount to a non-obvious leap of inference or “a bridge too far” that would require anything than the use of simple common sense to follow the clear teaching of the art.
For these reasons the rejections are deemed proper and maintained.
Furthermore even if it were assumed for the sake of argument that one of ordinary skill in the art would not in fact have regarded the disclosure of Liu et al. as suggesting the use of the claimed reaction conditions for displacement of a secondary alcohol, claim 1 would still be obvious for the reasons provided below:
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.
Claim 1 is are rejected under 35 U.S.C. 103 as being unpatentable over Gin et al. (PCT international publication WO2015/184451, reference included with PTO-1449 submitted March 22, 2023) in view of Rodriguez-Diaz et al. (Reference included with PTO-1449) in view of Tan et al. (PCT international publication WO2017/106836, reference included with PTO-1449 submitted March 22, 2023) in view of Chea et al. (Non-patent literature reference C10 cited in 3/22/2023 PTO-1449) in view of Adams et al. (Non-patent literature reference C3 cited in 3/22/2023 PTO-1449) In view of Squarcia et al. (Reference of record in previous action) in view of Scott et al. (Reference included with PTO-892)
Independent claim 1 is directed to a method of synthesizing a particular saponin compound, comprising purifying an aglycone compound (Quillaic acid) from Quillaja bark extract, and then carrying out a sequence of six chemical transformations on the compound so as to arrive at a specific product:
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Gin et al. discloses a minimal saponin analog compound having a structure:
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Wherein X can be an –NH-acyl group and Rn represents a hydrogen or saccharide. (p. 2 paragraph 5) In a specific embodiment the compound has the structure:
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Which when W is –C(=O)H and V is –OH, is similar to the compound produced by the process of claim 1, except that it contains a 6-aminohexanoic acid amide in place of a 1,12-dodecanedioic acid amide. (p. 4 paragraph 13) This compound can be made by a process starting from Quillaic acid (10):
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Which is subjected to TES-protection, coupling with a compound (12):
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Followed by reduction of the azide to an amine, coupling with a protected 6-aminohexanoic acid, and deprotection to form the final product. (pp. 26-28 paragraph 80, pp. 54-57 paragraphs 165-169) This process comprises the same steps recited in present claim 1 with the exception of the first purification step.
However, Rodriguez-Diaz et al. discloses that quillaic acid can be purified from a semi-purified Q. saponaria extract referred to as 100Q. (p. 719 under the headings “General procedures” and “isolation and characterization of quillaic acid (1)”) This purified compound is then used to synthesize a variety of derivatives which are tested for anti-inflammatory activity. (p. 721 figure 1, also the paragraph labeled “topical anti-inflammatory activity”) Therefore it would have been obvious to one of ordinary skill in the art at the time of the invention to perform a purification of quillaic acid from semi-purified extract 100Q or a similar semi-purified extract of Q. saponaria, and then to use the purified quillaic acid as a starting material in a synthesis according to Gin et al. One of ordinary skill in the art would have seen the disclosure of Gin et al. as suggesting using any existing prior art source of quillaic acid as a starting material because this reference uses this compound in its synthesis. Furthermore the fact that Rodriquez-Diaz et al. uses this compound as the starting material for synthesis for further biologically active compounds provides a reasonable expectation of success in using it as a starting material in the synthesis described by Gin et al.
The claimed invention also differs from that of Gin et al. in that the acid coupled to the amine group is 1,12-dodecanedioic acid rather than 6-aminohexanoic acid. However Tan et al. discloses similar saponin derivative compounds. (p. 2 paragraph 6) Specific embodiments of these compounds include those wherein the saccharide esterified at the carboxyl group of quillaic acid is the same dodecanedioic acid amidated trisaccharide appearing in the compound synthesized in the process of claim 1. (pp. 46-48 paragraph 159, especially compound (6)) This structure furthermore includes embodiments wherein G is hydrogen, which would correspond to the hydroxyl compounds synthesized in the presently claimed process. (p. 40 paragraph 137) When the dodecanedioic acid amide is used, it is formed by a step wherein the benzyl-protected carboxylic acid is coupled to the aminosugar moiety and then deprotected by reduction. (p. 94 paragraph 282., p. 96 paragraph 284, and reaction drawings immediately preceding these paragraphs)
It would have been obvious to one of ordinary skill in the art at the time of the invention to make a compound corresponding to the compound produced by Gin et al. wherein the 6-aminohexanoyl amide is replaced by a 12-carboxydecanoyl amide as described by Tan et al. One of ordinary skill in the art would have found it to be obvious to make such compounds because they fall within the generic disclosure of Tan et al., wherein G is hydrogen and Z is the dodecanedioic acid amide trisaccharide. Furthermore one of ordinary skill in the art would have found it to be obvious to apply the synthetic steps described by Gin et al. to the construction of these compounds as Gin et al. describes this synthetic scheme as being useful for producing a closely related compound.
With respect to the further limitation requiring that the compound C-1 be synthesized by the reaction steps:
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, Gin et al. does not specifically describe a method of making C-1 that requires these steps. However, Gin et al. does disclose this compound (compound 12 referenced in p. 59 paragraph 172) and describes it with reference to the reference Chea et al. (p. 44 paragraph 145) Chea et al. further discloses this trisaccharide as being made by a process (scheme 2 on p. 13451) involving a compound 20 which is described as being previously prepared with reference to the publication of Adams et al. (p. 13452, left column first paragraph, also citation 19 on p. 13456) Adams et al. discloses this compound as being prepared by a process including the steps:
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. (p. 1941 scheme 1) Squarcia et al. further discloses making a compound equivalent to compound 4 of Adams et al. by a process comprising reacting compound 3a:
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or 3b:
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by the process
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wherein condition a includes BzCl and pyridine and b includes sodium azide. (p. 4654 schemes 1 and 2) Therefore it would have been obvious to one of ordinary skill in the art, in carrying out the synthetic strategy described by Gin, to make the trisaccharide compound 12 by the steps described by Squarcia et al. One of ordinary skill in the art would have found this to be obvious because Gin et al. specifically suggests using synthetic routes of this type through reference to Chea, and then reference to Adams by the disclosure of Chea. While the synthetic steps described in Squarcia’s disclosure differ from the ones recited in present claim 1 by the use of MsCl followed by sodium azide to displace the hydroxide with azide, it is noted that both Adams and Squarcia report fairly low yields for the azide displacement reaction, which become even lower upon consideration of the requirement for an additional step to activate the hydroxyl as a mesylate. For example Squarcia’s method has an overall yield of 60%x50%, or 30%, for the conversion of the relevant diastereomer 3b to 7b.
Scott et al. discloses the synthesis of a HCV polymerase inhibitor which contains a seven-membered ring bearing an amine at a secondary carbon. (p. 1116 right column last paragraph, p. 1117 left column first paragraph, also scheme 1) Scott et al. furthermore discloses attempts to develop a more efficient large-scale synthesis of this compound by displacement of a hydroxyl group form the intermediate 3. (p. 1117 left column last paragraph) Attempting to carry out this reaction by activation of the alcohol as a mesylate and displacement by a nitrogen nucleophile failed because the mesylate was inert to such reactions or underwent elimination to an olefin. (p. 1118 left column third paragraph) By contrast the Mitsunobu reaction using DIAD/TPP/DPPA in THF, which are the same reaction conditions recited in present claim 1, proceeded with a typical yield of 95% for the azide.
Therefore it would have been obvious to one of ordinary skill in the art at the time of the invention to use the Mitsunobu reaction described by Scott et al. in place of the sodium azide displacement described by Adams and Squarcia. One of ordinary skill in the art would have regarded such a substitution as being obvious based on a rationale of applying a known improvement to a known process, as the synthetic step used by Adams and Squarcia is described as low yielding and the claimed reaction conditions are described by Scott as an improved alternative.
For these reasons the invention taken as a whole is prima facie obvious.
Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over Gin et al. ‘451 (PCT international publication WO2015/184451, reference included with PTO-1449 submitted March 22, 2023) in view of Rodriguez-Diaz et al. (Reference of record in PTO-1449 submitted March 22, 2023) in view of Gin et al. ‘585. (US pre-grant publication 2015/0086585, cited in PTO-1449 submitted March 22, 2023) in view of Chea et al. (Non-patent literature reference C10 cited in 3/22/2023 PTO-1449) in view of Adams et al. (Non-patent literature reference C3 cited in 3/22/2023 PTO-1449) In view of Squarcia et al. (Reference of record in previous action) in view of Scott et al. (Reference included with PTO-892)
Independent claim 1 is directed to a method of synthesizing a particular saponin compound, comprising purifying an aglycone compound (Quillaic acid) from Quillaja bark extract, and then carrying out a sequence of six chemical transformations on the compound so as to arrive at a specific product:
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Gin et al. ‘451 discloses a minimal saponin analog compound having a structure:
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Wherein X can be an –NH-acyl group and Rn represents a hydrogen or saccharide. (p. 2 paragraph 5) In a specific embodiment the compound has the structure:
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Which when W is –C(=O)H and V is –OH, is similar to the compound produced by the process of claim 1, except that it contains a 6-aminohexanoic acid amide in place of a 1,12-dodecanedioic acid amide. (p. 4 paragraph 13) This compound can be made by a process starting from Quillaic acid (10):
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Which is subjected to TES-protection, coupling with a compound (12):
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Followed by reduction of the azide to an amine, coupling with a protected 6-aminohexanoic acid, and deprotection to form the final product. (pp. 26-28 paragraph 80, pp. 54-57 paragraphs 165-169) This process comprises the same steps recited in present claim 1 with the exception of the first purification step.
However, Rodriguez-Diaz et al. discloses that quillaic acid can be purified from a semi-purified Q. saponaria extract referred to as 100Q. (p. 719 under the headings “General procedures” and “isolation and characterization of quillaic acid (1)”) This purified compound is then used to synthesize a variety of derivatives which are tested for anti-inflammatory activity. (p. 721 figure 1, also the paragraph labeled “topical anti-inflammatory activity”) Therefore it would have been obvious to one of ordinary skill in the art at the time of the invention to perform a purification of quillaic acid from semi-purified extract 100Q or a similar semi-purified extract of Q. saponaria, and then to use the purified quillaic acid as a starting material in a synthesis according to Gin et al. ‘451. One of ordinary skill in the art would have seen the disclosure of Gin et al. as suggesting using any existing prior art source of quillaic acid as a starting material because this reference uses this compound in its synthesis. Furthermore the fact that Rodriquez-Diaz et al. uses this compound as the starting material for synthesis for further biologically active compounds provides a reasonable expectation of success in using it as a starting material in the synthesis described by Gin et al. ‘451.
The claimed invention also differs from that of Gin et al. ‘451 in that the acid coupled to the amine group is 1,12-dodecanedioic acid rather than 6-aminohexanoic acid. However Gin et al. ‘585 discloses quillaja saponins derivatives of a similar structure. (p. 1 paragraph 8 – p. 2 paragraph 31) Furthermore derivatives are disclosed having no saccharide group at position C3, corresponding to the free hydroxyl continuing compounds described by Gin et al. ‘451 and instant claim 1. (p. 20 paragraph 234, p. 25 compound I-14) Furthermore Gin et al. ‘585 describes embodiments wherein the amide group on the aminosugar moiety is an alkylenedioic acid amide having 3-15 carbons, which encompasses the dodecanedioic acid amide of the instant claims. (p. 18 paragraph 217)
It would have been obvious to one of ordinary skill in the art at the time of the invention to make a compound corresponding to the compound produced by Gin et al. ‘451 wherein the 6-aminohexanoyl amide is replaced by a 12-carboxydecanoyl amide as described by Gin et al. ‘585. One of ordinary skill in the art would have found it to be obvious to make such compounds because they fall within the generic disclosure of Gin et al. 585, wherein G is hydrogen and Z is the dodecanedioic acid amide trisaccharide. Furthermore one of ordinary skill in the art would have found it to be obvious to apply the synthetic steps described by Gin et al. ‘451 to the construction of these compounds as Gin et al. ‘451 describes this synthetic scheme as being useful for producing a closely related compound.
With respect to the further limitation requiring that the compound C-1 be synthesized by the reaction steps:
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, Gin et al. does not specifically describe a method of making C-1 that requires these steps. However, Gin et al. does disclose this compound (compound 12 referenced in p. 59 paragraph 172) and describes it with reference to the reference Chea et al. (p. 44 paragraph 145) Chea et al. further discloses this trisaccharide as being made by a process (scheme 2 on p. 13451) involving a compound 20 which is described as being previously prepared with reference to the publication of Adams et al. (p. 13452, left column first paragraph, also citation 19 on p. 13456) Adams et al. discloses this compound as being prepared by a process inc