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 .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-22) in the reply filed on 3 June 2026 is acknowledged.
Claims 23-24 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 3 June 2026.
Claim Rejections - 35 USC § 103
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 (i.e., changing from AIA to pre-AIA ) 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.
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.
Claims 1–14 and 16–22 is/are rejected under 35 U.S.C. § 103 as being unpatentable over Grotjahn, U.S. Publication No. 2010/0228031, in view of Shchepinov, U.S. Publication No. 2011/0105609, and further in view of Erdogan and Grotjahn, “Mild and Selective Deuteration and Isomerization of Alkenes by a Bifunctional Catalyst and Deuterium Oxide,” J. Am. Chem. Soc. 2009, 131, pgs. 10354–10355.
Grotjahn teaches transition-metal catalysts, particularly ruthenium-comprising catalysts, for treating polyunsaturated organic molecules, including polyunsaturated fatty-acid derivatives, natural fats, and natural oils containing two or more carbon-carbon double bonds. Grotjahn specifically identifies linoleic acid, linolenic acid, fatty acids, fatty-acid esters, triglycerides, fats, oils, linoleic-acid-containing materials, and methyl linoleate as suitable substrates. See Grotjahn, Abstract, PDF p. 1; ¶¶ [0001] and [0005]–[0007], PDF p. 2; and ¶¶ [0025]–[0031], PDF p. 4.
Grotjahn further teaches that the catalysts may be used for exchange of alkene hydrogens with deuterium or tritium and expressly states that deuterated water may be added to an isomerization reaction mixture to form deuterated hydrocarbon species. See Grotjahn, Abstract, PDF p. 1; ¶ [0001], PDF p. 2; and ¶ [0072], PDF p. 7. Example 9 demonstrates the isotope-exchange capability by reacting 1-pentene with 5 mol% of the Formula IV ruthenium catalyst and ten equivalents of D₂O at room temperature. Grotjahn reports complete isomerization within one hour followed by incorporation of deuterium into all alkene positions accessible through the isomerization process. See Grotjahn ¶¶ [0156]–[0157], PDF p. 16.
Grotjahn does not expressly demonstrate direct D₂O-mediated isotope exchange on a polyunsaturated lipid while retaining the methylene-interrupted PUFA structure. Grotjahn’s linoleic-acid experiment in Example 10 was instead directed to conjugation, used acetone-d₆ without added D₂O, was conducted at 70°C, and reported preservation of the allylic proton integrations. See Grotjahn ¶¶ [0158]–[0160], PDF pp. 16–17. Thus, Grotjahn does not alone expressly teach the claimed site-specific PUFA product.
Shchepinov teaches the particular isotopically modified PUFA products and substitution sites that Grotjahn does not expressly identify. Shchepinov explains that the oxidation-sensitive positions of PUFAs are the bis-allylic positions and that isotope reinforcement at those positions increases resistance to oxidation. Shchepinov specifically discloses 11,11-dideutero-linoleic acid, designated D₂-LA, and 11,11,14,14-tetradeutero-alpha-linolenic acid, designated D₄-ALA, wherein both hydrogens at each selected bis-allylic methylene position are replaced by deuterium. See Shchepinov ¶ [0084], PDF p. 21.
Shchepinov also discloses isotope-reinforced omega-3 and omega-6 PUFAs, including deuterated arachidonic-acid and linolenic-acid species; heavy-isotope enrichment between 50% and 99% at the reinforced positions; and ethyl-ester and glyceryl-ester forms of the modified fatty acids. See Shchepinov ¶ [0089], PDF p. 22; ¶ [0095], PDF p. 24; and ¶ [0100], PDF p. 24.
Erdogan and Grotjahn expressly teach that H/D exchange occurs at allylic positions of alkenes using D₂O in acetone and a bifunctional imidazolylphosphine CpRu catalyst. Erdogan reports an exceptional degree of controlled deuteration at positions accessible through alkene isomerization. See Erdogan and Grotjahn, p. 10354, Abstract.
It would have been obvious to one of ordinary skill in the art before the effective filing date to apply the D₂O-mediated catalytic H/D-exchange method taught by Grotjahn and Erdogan to the polyunsaturated fatty-acid substrates expressly identified by Grotjahn in order to prepare the known bis-allylicly deuterated PUFA products taught by Shchepinov.
Shchepinov provides an express reason for targeting the bis-allylic positions: replacement of the oxidation-sensitive bis-allylic hydrogens with deuterium produces PUFAs having increased resistance to oxidation. Grotjahn identifies the same class of methylene-interrupted PUFA substrates and expressly instructs that D₂O may be added to its transition-metal-catalyzed isomerization reaction to form deuterated products. Erdogan confirms that the disclosed bifunctional CpRu catalyst performs controlled H/D exchange specifically at allylic positions using D₂O. The combined teachings therefore would have directed the skilled artisan to use Grotjahn’s catalyst and D₂O with a PUFA substrate to place deuterium at allylic positions, including the bis-allylic methylene positions identified by Shchepinov.
There also would have been a reasonable expectation of success. Grotjahn demonstrates that the catalyst acts on PUFA substrates and separately demonstrates D₂O-mediated isotope exchange with the same type of catalyst. Erdogan expressly establishes the allylic positional selectivity of that isotope-exchange reaction. Although Grotjahn’s Example 10 preserved allylic protons during conjugation of linoleic acid, that experiment did not employ the D₂O exchange conditions relied upon in the proposed combination. It instead used acetone-d₆ at 70°C and was directed to conjugating the double bonds. The Example 10 result therefore would not have discouraged the skilled artisan from using the expressly taught D₂O exchange conditions of Example 9 and Erdogan.
The proposed combination is not based merely on the independent existence of the claim elements. Rather, Grotjahn expressly links its catalyst systems to PUFA substrates and isotope exchange, Shchepinov identifies the specific beneficial isotope-substitution sites and products, and Erdogan confirms that the catalyst/D₂O system exchanges allylic hydrogens. These findings provide an articulated reason to combine the references and a reasonable expectation of obtaining isotope incorporation at an allylic or bis-allylic site.
Claim 1
Regarding claim 1, Grotjahn teaches reacting a polyunsaturated lipid, including a polyunsaturated fatty acid, fatty-acid derivative, natural fat, or natural oil, in the presence of a transition-metal-based catalyst, particularly a ruthenium catalyst. See Grotjahn ¶¶ [0005]–[0007], PDF p. 2, and ¶¶ [0025]–[0030], PDF p. 4.
Grotjahn teaches exchanging alkene hydrogens for deuterium or tritium, adding D₂O to an isomerization reaction mixture to form deuterated hydrocarbon species, and using a Formula IV ruthenium catalyst with D₂O to incorporate deuterium at positions accessible through alkene isomerization. See Grotjahn ¶ [0001], PDF p. 2; ¶ [0072], PDF p. 7; and ¶¶ [0156]–[0157], PDF p. 16.
Grotjahn does not expressly teach that application of the exchange reaction to a PUFA produces a PUFA having isotope at a mono-allylic or bis-allylic site. Shchepinov teaches PUFAs having deuterium at one or more bis-allylic sites and identifies such positions as the desired oxidation-sensitive sites for isotope reinforcement. See Shchepinov ¶ [0084], PDF p. 21. Erdogan further teaches that the catalyst/D₂O reaction produces H/D exchange at allylic positions. See Erdogan, p. 10354, Abstract. Accordingly, the combined references teach or suggest every limitation of claim 1.
Claim 2
Regarding claim 2, Grotjahn teaches that the polyunsaturated substrate may be a fatty acid or fatty-acid ester and specifically teaches treating natural fats and oils in acid or ester form. See Grotjahn ¶ [0007], PDF p. 2, and ¶¶ [0029]–[0030], PDF p. 4. Either the fatty-acid or fatty-acid-ester alternative satisfies the closed group recited in claim 2.
Claim 3
Regarding claim 3, Grotjahn expressly teaches polyunsaturated organic molecules comprising two or more skipped or nonconjugated carbon-carbon double bonds. See Grotjahn ¶ [0025], PDF p. 4.
Claim 4
Regarding claim 4, Shchepinov expressly discloses D₄-alpha-linolenic acid, which contains three carbon-carbon double bonds. See Shchepinov ¶ [0084], PDF p. 21. Grotjahn also states that its polyunsaturated substrates may contain two, three, or more carbon-carbon double bonds. See Grotjahn Abstract, PDF p. 1, and ¶ [0068], PDF pp. 6–7.
Claim 5
Regarding claim 5, Grotjahn expressly identifies linoleic acid and methyl linoleate as suitable polyunsaturated substrates. See Grotjahn ¶¶ [0007] and [0030], PDF pp. 2 and 4. Linoleic acid is a species within Formula (IA), including the claimed terminal alkyl group, carboxylic-acid group, methylene segments, and plurality of carbon-carbon double bonds. Methyl linoleate similarly falls within the ester alternative of Formula (IA). Disclosure of a species within the claimed genus renders the genus limitation obvious.
Claim 6
Regarding claim 6, Shchepinov expressly teaches isotope-reinforced omega-3 and omega-6 essential PUFAs. See Shchepinov ¶ [0089], PDF p. 22. Disclosure of either recited alternative satisfies the Markush limitation.
Claim 7
Regarding claim 7, Grotjahn expressly identifies fatty-acid derivatives of linoleic and linolenic acid as substrates for its bifunctional catalyst system. See Grotjahn ¶ [0007], PDF p. 2. Shchepinov additionally discloses D₂-linoleic acid and D₄-alpha-linolenic acid. See Shchepinov ¶ [0084], PDF p. 21.
Claim 8
Regarding claim 8, Shchepinov expressly discloses deuterated arachidonic-acid species, which satisfy one alternative of the closed group recited in claim 8. See Shchepinov ¶ [0089], PDF p. 22, particularly the structures identified under “D-Arachidonic acids.”
Claim 9
Regarding claim 9, Grotjahn expressly teaches that the polyunsaturated organic molecule may be a triglyceride, fat, oil, or derivative thereof. See Grotjahn ¶ [0029], PDF p. 4, and ¶ [0061], PDF p. 6. The triglyceride alternative satisfies the limitation of claim 9.
Claim 10
Regarding claim 10, Grotjahn teaches carrying out the process on fatty-acid esters and specifically exemplifies methyl-ester forms. See Grotjahn ¶ [0007], PDF p. 2, and ¶ [0030], PDF p. 4. Shchepinov teaches that an ethyl ester is a known, pharmaceutically suitable ester form of an isotopically modified PUFA. See Shchepinov ¶ [0100], PDF p. 24.
It would have been obvious to substitute the known ethyl ester for Grotjahn’s methyl ester because both are conventional lower-alkyl fatty-acid esters, Grotjahn expressly permits ester-form substrates generally, and Shchepinov identifies the ethyl ester as a suitable form of the desired modified PUFA. The substitution would have predictably provided the corresponding deuterated PUFA ethyl ester.
Claim 11
Regarding claim 11, Shchepinov expressly teaches deuterated PUFAs having deuterium at one or more bis-allylic sites, including D₂-linoleic acid and D₄-alpha-linolenic acid. See Shchepinov ¶ [0084], PDF p. 21.
Claim 12
Regarding claim 12, Shchepinov teaches D₄-alpha-linolenic acid in which both hydrogen atoms at each bis-allylic methylene position are replaced with deuterium. See Shchepinov ¶ [0084], PDF p. 21. Thus, the disclosed D₄-alpha-linolenic acid has deuterium at all bis-allylic sites.
Shchepinov’s NMR discussion further states that deuteration at both the C11 and C14 positions results in disappearance of the corresponding signals, corroborating substitution at both bis-allylic positions. See Shchepinov ¶ [0147], PDF p. 32.
Claim 13
Regarding claim 13, Erdogan teaches H/D exchange at allylic positions of alkenes using D₂O and the bifunctional imidazolylphosphine CpRu catalyst. Erdogan further teaches that deuteration occurs with a high degree of control at positions accessible through isomerization. See Erdogan, p. 10354, Abstract. Grotjahn likewise reports deuterium incorporation into all alkene positions accessible through isomerization. See Grotjahn ¶ [0157], PDF p. 16.
A polyunsaturated lipid includes mono-allylic positions adjacent to its terminal double bonds. It would have been expected that application of the disclosed allylic-exchange method to the PUFA would exchange at least one accessible mono-allylic hydrogen in addition to, or as an alternative to, exchange at a bis-allylic position. The combined references therefore render the limitation of claim 13 obvious.
Claim 14
Regarding claim 14, Shchepinov teaches heavy-isotope enrichment between 50% and 99% at the reinforced PUFA positions. See Shchepinov ¶ [0095], PDF p. 24. That range includes values greater than 50% and therefore overlaps the claimed range. Selection of a value within the expressly disclosed overlapping range would have been prima facie obvious.
Claim 16
Regarding claim 16, Grotjahn principally teaches ruthenium catalysts and further teaches that ruthenium may be replaced by transition metals including rhodium, iridium, nickel, palladium, and platinum. See Grotjahn ¶ [0023], PDF p. 4. Ruthenium alone is sufficient to satisfy the closed group recited in claim 16.
Claim 17
Regarding claim 17, Grotjahn expressly prepares and uses ruthenium-comprising CpRu catalyst complexes, including the Formula IV catalyst. See Grotjahn ¶ [0140], PDF p. 14, and ¶ [0157], PDF p. 16.
Claim 18
Regarding claim 18, Grotjahn teaches cationic ruthenium complexes containing a ring ligand, independently selected neutral or anionic ligands, and a charge-balancing anion. Grotjahn teaches acetonitrile, alkene, phosphine, heterocyclic, and other neutral-ligand alternatives and teaches the presence of an anion sufficient to balance the catalyst charge. See Grotjahn ¶¶ [0008]–[0009], PDF p. 3.
Grotjahn further teaches that the Cp ligand in its catalyst formulas may be replaced by benzene or a substituted benzene derivative. See Grotjahn ¶ [0010], PDF p. 3. Benzene provides the claimed C₆ aryl L¹ ligand. The Formula IV complex contains ruthenium, an imidazolylphosphine ligand, acetonitrile, and a PF₆⁻ counterion. See Grotjahn ¶ [0140], PDF p. 14. Accordingly, Grotjahn teaches or suggests a complex within Formula (IIA) wherein M is ruthenium; L¹ is a C₆ aryl ligand; L² comprises phosphine, heterocyclic, and/or acetonitrile ligand functionality; m is within 1–3; Q is a singly charged anion; and n is 1.
Claim 19
For purposes of examination over the prior art, and without withdrawing the separate §§ 112(b) and 112(d) rejections, claim 19 is interpreted as requiring that M of Formula (IIA) be ruthenium.
Under that interpretation, Grotjahn expressly teaches ruthenium as the metal center of its Formula IV catalyst. See Grotjahn ¶ [0140], PDF p. 14.
Claim 20
For purposes of examination over the prior art, and without withdrawing the separate §§ 112(b) and 112(d) rejections, claim 20 is interpreted as limiting an L² ligand of Formula (IIA) to a phosphine of the recited —P(R⁴)₃ form.
Grotjahn teaches an imidazolylphosphine ligand in which phosphorus is bonded to carbon substituents, including isopropyl groups, and expressly teaches phosphine-containing heterocyclic ligands. See Grotjahn ¶¶ [0008]–[0010], PDF p. 3, and ¶ [0140], PDF p. 14. The disclosed phosphine has three carbon substituents on phosphorus and falls within the broad —P(R⁴)₃ limitation and R⁴ definitions of claim 20.
Claim 21
Regarding claim 21, Grotjahn expressly teaches adding deuterated water to an isomerization reaction mixture and expressly uses D₂O in Example 9. See Grotjahn ¶ [0072], PDF p. 7, and ¶ [0157], PDF p. 16. D₂O is one of the alternatives expressly recited in claim 21.
Claim 22
Regarding claim 22, Grotjahn teaches applying its transition-metal catalyst system to natural fats and oils, including linseed, fish, soybean, corn, sunflower, safflower, castor, and other oils or fats. See Grotjahn ¶ [0007], PDF p. 2; ¶¶ [0029]–[0030], PDF p. 4; ¶ [0061], PDF p. 6; and ¶ [0068], PDF pp. 6–7. Natural fats and oils comprise mixtures of lipid species and therefore constitute polyunsaturated lipid mixtures rather than only a single purified lipid.
Grotjahn further teaches adding D₂O to the catalyst reaction mixture and demonstrates the isotope-exchange capability of the catalyst/D₂O system. See Grotjahn ¶ [0072], PDF p. 7, and ¶ [0157], PDF p. 16. Shchepinov supplies the known desirability of producing bis-allylicly deuterated PUFA components, and Erdogan establishes allylic H/D exchange under the catalyst/D₂O conditions.
It would have been obvious to subject Grotjahn’s expressly disclosed natural fat or oil mixture to the disclosed D₂O-mediated exchange conditions. Processing the lipid components together would have used the catalyst for its disclosed isotope-exchange function on the natural lipid-mixture substrates that Grotjahn already identifies for catalytic treatment, thereby producing an isotopically modified polyunsaturated lipid mixture.
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.
Claims 1–22 rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1–14 and 20 of U.S. Patent No. 10,730,821 B2, and, as to claims 9 and 22, further in view of Grotjahn and Shchepinov.
U.S. Patent No. 10,730,821 B2 claim 1 claims a method for reacting a Formula (IA) polyunsaturated lipid with D₂O, a deuterated alcohol, T₂O, or a tritiated alcohol in the presence of a Formula (IIA) ruthenium catalyst to obtain isotope substitution at one or more mono-allylic or bis-allylic sites. Patent claims 2–14 further claim the same substrate, positional-deuteration, enrichment, and catalyst limitations now presented in the pending claims. Patent claim 20 claims that the method obtains a mixture of isotopically modified PUFAs. See U.S. Patent No. 10,730,821 B2, claims 1–20, PDF pp. 29–30, particularly p. 29, lines 1368–1408, and p. 30, lines 1420–1432.
The pending application is a continuation of U.S. Application No. 17/884,959 through an uninterrupted continuation chain that includes the application issuing as U.S. Patent No. 10,730,821 B2. The two matters identify the same inventors and claim the same November 23, 2015 priority date. Because the current application has the same or later patent-term filing date, the one-way test is applicable: whether each pending claim is anticipated by or would have been an obvious variation of a claim of the reference patent. MPEP § 804 states that an examined genus is not patentably distinct from a species or subgenus claimed in the reference patent where the reference claim’s scope falls within the examined genus.
Pending claim 1 is broader than and encompasses the complete method of patent claim 1. Patent claim 1 requires a Formula (IA) PUFA, one of the isotope agents encompassed by pending claim 1, a Formula (IIA) ruthenium catalyst, and isotope substitution at a mono-allylic or bis-allylic site. Every performance of patent claim 1 therefore performs pending claim 1. Pending claim 1 is anticipated, for double-patenting purposes, by the species and subgenus of patent claim 1.
Pending claim 2 is not patentably distinct from patent claims 7 and 8. Patent claim 7 limits the PUFA to a fatty-acid alkyl ester, and patent claim 8 limits the ester to an ethyl ester. Those claimed species fall wholly within the fatty-acid-ester alternative of pending claim 2.
Pending claim 3 corresponds to patent claim 2, which requires two or more carbon-carbon double bonds.
Pending claim 4 corresponds to patent claim 3, which requires at least three carbon-carbon double bonds.
Pending claim 5 is not patentably distinct from patent claim 1, which expressly requires the PUFA to have Formula (IA) and defines R¹, R², R³, n, and p using the same or narrower alternatives.
Pending claim 6 is not patentably distinct from patent claim 4. Patent claim 4 expressly claims omega-3, omega-6, and omega-9 fatty acids and their esters. At minimum, the acid alternatives expressly claimed in patent claim 4 fall within pending claim 6, and selection of the acid form from the expressly claimed acid/ester alternatives would have been immediately apparent.
Pending claim 7 is not patentably distinct from patent claim 5, which expressly claims linoleic acid and linolenic acid and their esters.
Pending claim 8 is not patentably distinct from patent claim 6. Patent claim 6 expressly claims gamma-linolenic acid, dihomo-gamma-linolenic acid, arachidonic acid, and docosatetraenoic acid, among other alternatives. Those species are expressly recited in pending claim 8.
Pending claim 9 is not patentably distinct from patent claim 1 in view of Grotjahn. Patent claim 1 claims the direct catalytic isotope-exchange process for a Formula (IA) PUFA. Grotjahn establishes that triglycerides were known PUFA substrates for transition-metal treatment. See Grotjahn ¶ 0029, p. 3, lines 318–320, and ¶ 0061, p. 5, lines 458–463. It would have been obvious to carry out the claimed patent process using the known triglyceride form of the PUFA.
Pending claim 10 corresponds to patent claim 8, which expressly requires an ethyl ester.
Pending claim 11 corresponds to patent claim 9, which requires deuteration at one or more bis-allylic sites.
Pending claim 12 corresponds to patent claim 10, which requires deuteration at all bis-allylic sites.
Pending claim 13 is broader than and encompasses patent claim 11. Patent claim 11 requires deuteration at one or more mono-allylic sites in addition to bis-allylic deuteration. The presence of the additional bis-allylic deuteration does not remove the method from the scope of pending claim 13, which requires only that one or more mono-allylic sites be deuterated.
Pending claim 14 corresponds to patent claim 12, which requires more than 50% deuteration at bis-allylic sites.
Pending claim 15 corresponds to patent claim 13, which expressly requires less than 30% deuteration at mono-allylic sites. Although pending claim 15 is not included in the separate prior-art rejection above, it is directly subject to the double-patenting rejection.
Pending claim 16 is generic to the ruthenium species claimed in patent claim 1. Because ruthenium is one of the metals in pending claim 16, every method within patent claim 1 also meets pending claim 16.
Pending claim 17 is anticipated, for double-patenting purposes, by patent claim 1, which expressly requires M to be ruthenium.
Pending claim 18 is not patentably distinct from patent claim 1. Patent claim 1 expressly claims Formula (IIA), M as ruthenium, L¹ as cyclopentadienyl or C₆–₁₀ aryl, the recited broad L² ligand genus, m from 1 to 3, a singly charged Q anion, and n of zero or one. At least the expressly claimed C₆–₁₀ aryl species falls within the L¹ genus of pending claim 18, and the remaining Formula (IIA) variables are identical to or narrower than those of pending claim 18.
Pending claim 19, under its apparent intended construction, corresponds to patent claim 1 because patent claim 1 requires M to be ruthenium.
Pending claim 20, under its apparent intended construction, corresponds to patent claim 14, which expressly claims L² as —P(R⁴)₃ and defines R⁴ using the same substituent alternatives.
Pending claim 21 is anticipated, for double-patenting purposes, by patent claim 1, which expressly limits the isotope-containing agent to D₂O, DO–C₁–₁₀ alkyl, T₂O, or TO–C₁–₁₀ alkyl—the same alternatives recited in pending claim 21.
Pending claim 22 is not patentably distinct from patent claims 1 and 20 in view of Grotjahn and Shchepinov. Patent claim 1 claims the direct catalytic isotope-exchange method, and patent claim 20 expressly requires the method to obtain a mixture of isotopically modified PUFAs. The remaining difference is pending claim 22’s express requirement that the starting material itself be a PUFA mixture. Grotjahn teaches applying the catalyst to natural fats and oils containing multiple lipid components, and Shchepinov expressly teaches mixtures of D₂-linoleic acid and D₄-linolenic acid. See Grotjahn ¶ 0007, p. 1, lines 131–143; ¶ 0061, p. 5, lines 458–463; and Shchepinov p. 34, lines 2262–2277. Processing the known PUFA components together, instead of separately, would have been a predictable and economical variation of the method claimed in patent claims 1 and 20.
Accordingly, claims 1–22 do not define patentably distinct subject matter from the claims of U.S. Patent No. 10,730,821 B2.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-22 are rejected under 35 U.S.C. § 112(a) because the specification, while being enabling for site-specific deuteration of certain polyunsaturated lipid substrates using D₂O and particular ruthenium catalysts under the disclosed reaction conditions, does not reasonably provide enablement for the full scope of the claimed methods. The specification does not enable a person of ordinary skill in the art to make and use the invention throughout the full catalyst, lipid-substrate, isotope-source, and reaction scope encompassed by the claims without undue experimentation.
Independent claim 1 broadly encompasses reacting any “polyunsaturated lipid,” as that term is defined in the specification, with an isotope-containing agent comprising deuterium, tritium, or combinations thereof, in the presence of any transition metal-based catalyst capable of producing isotope incorporation at one or more mono-allylic or bis-allylic sites. Independent claim 22 contains corresponding breadth with respect to mixtures of polyunsaturated lipids. Claims 2-10 encompass, among other subject matter, fatty acids, esters, thioesters, amides, mimetics, prodrugs, glycerides, ethyl esters, and broad structural genera. Claims 16-18 encompass numerous metal genera, combinations of metals, and a broad coordination-complex genus containing numerous ligand classes. Claim 21 expressly encompasses D₂O, deuterated alcohols, T₂O, and tritiated alcohols.
The specification provides meaningful operative guidance for a substantially narrower portion of that scope. Example 2 principally concerns H/D exchange using D₂O in acetone and six ruthenium-based complexes. The successful preparative examples principally employ complex 4 with ethyl linolenate, ethyl arachidonate, ethyl docosahexaenoate, trilinolenin, and a mixture of ethyl linolenate, ethyl arachidonate, and ethyl docosahexaenoate. The specification reports approximately 94-98% bis-allylic deuteration for certain substrates and identifies complex 4 as more effective than the other tested catalysts.
The specification does not provide a working example demonstrating the claimed direct isotope-exchange method using tritium; T₂O or a tritiated alcohol; a deuterated alcohol as the isotope-containing agent; a fatty acid thioester, amide, mimetic, or prodrug; or a catalyst based on rhodium, iridium, nickel, platinum, palladium, aluminum, titanium, zirconium, or hafnium within the broadly claimed direct catalytic process. Nor does the specification establish a recognized structure-function relationship by which a skilled artisan could determine, without extensive screening, which members of the claimed catalyst genera would provide the required isotope incorporation while avoiding conjugation, double-bond migration, or cis-trans isomerization.
The determination that undue experimentation would be required is based on the following factors set forth in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Breadth of the claims
The breadth of the claims weighs heavily against enablement. Claims 1 and 22 are not limited to the particular ruthenium catalysts, D₂O source, solvent, temperature, catalyst loading, or PUFA substrates demonstrated in the working examples. The claims encompass broad combinations of structurally and electronically different transition-metal catalysts, lipid classes, isotope sources, and substrates. Claim 18 further encompasses a large coordination-complex genus produced by combining numerous metals, ligand types, substituents, ligand numbers, and counterion states. The full scope therefore includes an extensive number of materially different reaction systems beyond those demonstrated in the specification.
Nature of the invention
The nature of the invention weighs against enablement. The claimed invention concerns site-selective catalytic isotope exchange in unsaturated lipid systems. The specification explains that these systems present both thermodynamic and selectivity problems because the desired cis, methylene-interrupted double-bond arrangement is less thermodynamically favored than conjugated or trans-containing arrangements, and because catalytic intermediates may not readily distinguish mono-allylic from bis-allylic positions. The desired result therefore depends on the coordinated interaction among the substrate, metal center, ligand environment, isotope source, solvent, temperature, and reaction time.
State of the prior art
The state of the art, as described by the specification, weighs against enablement. The disclosure acknowledges difficulties associated with selectively labeling highly unsaturated fatty acids and avoiding chromatographic purification, isomerization, and conjugation. Although catalytic isotope exchange was known for other organic substrates, the disclosure indicates that the operative mechanism for complex 4 may differ from mechanisms previously described for other substrates. The specification therefore does not establish that the claimed results were routinely predictable throughout the claimed metal, ligand, lipid, and isotope genera.
Level of ordinary skill
The level of ordinary skill is reasonably high and would include substantial training or experience in synthetic organic chemistry, organometallic catalysis, isotope chemistry, lipid chemistry, and analytical characterization. This factor weighs in favor of enablement to some degree. Nevertheless, a high level of skill does not supply the missing information concerning which combinations within the broad claimed genera will perform the required site-specific exchange, particularly where the specification’s own comparative results show that closely related catalysts produce substantially different outcomes.
Level of predictability
The predictability of the art weighs heavily against enablement. The specification reports that complex 5 showed no deuteration ability with ethyl linolenate, while the permethylated analogue identified as complex 6 produced cis-trans isomerization rather than the target deuteration. Complex 1 produced conjugation with ethyl linoleate, whereas complexes 2-4 produced materially different positional-deuteration results. The same catalyst also behaved differently depending on substrate structure: complex 4 deuterated ethyl linoleate principally at mono-allylic sites but deuterated substrates containing three or more double bonds principally at bis-allylic sites. These results establish that activity and selectivity cannot be reliably predicted merely from the presence of a transition metal or from general membership in the claimed ligand classes.
Amount of direction or guidance
The amount of direction weighs partly in favor of enablement for the specifically demonstrated embodiments but against enablement for the full claimed scope. The specification provides useful procedures for complex 4, D₂O, acetone, and certain PUFA esters and triglycerides. It also teaches catalyst loadings, reaction temperatures, workup procedures, and NMR monitoring for those embodiments. However, it provides no comparable operative guidance for selecting catalysts based on most of the other claimed metals, selecting functional combinations from the Formula (IIA) genus, adapting the process to the untested lipid classes, or employing the alternative isotope-containing agents of claim 21. The broad lists of possible metals, ligands, substrates, and isotope sources do not provide sufficient guidance concerning which combinations will achieve the claimed result.
Existence of working examples
The existence of working examples weighs in favor of enablement for a limited portion of the claims. Example 2 demonstrates deuteration using several ruthenium complexes and provides successful preparative examples using complex 4 and D₂O. It also demonstrates one mixture containing three PUFA ethyl esters. The examples, however, occupy only a narrow portion of the claimed scope and do not demonstrate the other claimed metal classes, isotope sources, or substantial portions of the claimed lipid genera. The examples also include unsuccessful or undesired results, including no deuteration, conjugation, and cis-trans isomerization.
Quantity of experimentation
The quantity of experimentation required weighs against enablement. To practice the full scope, a skilled artisan would be required to select and prepare catalysts across numerous metal and ligand genera; determine oxidation states, ligand combinations, counterions, catalyst loadings, solvents, temperatures, and reaction times; test multiple isotope sources; and separately evaluate the numerous lipid classes and mixtures. Each combination would require analytical determination of isotope incorporation, positional selectivity, double-bond migration, conjugation, and stereoisomerization. Because closely related catalysts produced no reaction or undesired isomerization, this work would not merely involve routine optimization of a known operative embodiment. Rather, it would amount to an extensive research and screening program to identify operative combinations within the claimed scope.
When the above factors are considered as a whole, the disclosure does not enable the full scope of claims 1-22 without undue experimentation. The specification reasonably enables, at most, the demonstrated deuteration processes employing D₂O and selected ruthenium catalysts, particularly complex 4, with the disclosed PUFA substrates and mixtures under conditions comparable to those taught in Example 2. It does not provide enablement commensurate with the substantially broader scope sought by the claims. The USPTO applies the Wands factors to determine whether the full claimed scope can be made and used without unreasonable or undue experimentation, and a scope-of-enablement rejection must identify both the enabled and nonenabled subject matter, as set forth above.
Claims 2-15 do not overcome the deficiency because they retain the unrestricted catalyst scope of claim 1 and, except to the extent expressly narrowed, retain broad substrate and isotope-source scope. Claim 17 narrows claim 16 to ruthenium but continues to encompass an unrestricted genus of ruthenium catalysts; the specification itself establishes that not every tested ruthenium complex performs the claimed isotope incorporation. Claim 18 encompasses an extensive catalyst genus extending well beyond the operative examples. Claim 21 affirmatively recites isotope sources for which the specification supplies no working example. Claim 22 likewise encompasses mixtures generally, while the working disclosure demonstrates only a single three-component mixture using complex 4 and D₂O.
For claims 19 and 20, the rejection is made on the interpretation that “M” and “L²” are intended to refer to the catalyst variables defined in Formula (IIA) of claim 18. The claims are separately rejected as indefinite below. If applicant contends that a different construction is intended, applicant is required to clarify the scope of those claims.
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 19-20 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 19 depends directly from claim 1 and recites “wherein M is ruthenium.” Claim 1 does not introduce the variable M, does not recite Formula (IIA), and does not associate M with the transition metal-based catalyst. The variable M is introduced only in claim 18 as part of Formula (IIA). It is therefore unclear from the language of claim 19 what element of the claim 1 method is required to be ruthenium. Although the specification may indicate the probable intended relationship, limitations from the specification or another claim cannot be imported into claim 19 to repair its dependency.
Claim 20 likewise depends directly from claim 1 and recites “wherein L² is —P(R⁴)₃.” Claim 1 does not introduce L², Formula (IIA), or any ligand represented by L². L² is introduced only in claim 18 as a ligand variable in Formula (IIA). It is therefore unclear what component of the method of claim 1 is being limited by the recitation concerning L². A lack of antecedent basis warrants a rejection where, as here, the absent relationship prevents the scope from being reasonably ascertained.
Claim 20 is additionally indefinite because the claim does not clearly establish whether one L² ligand or every L² ligand is required to be —P(R⁴)₃. Formula (IIA) employs the term [ML1(L²) m]Q3, claim 18 states that “each L²” is independently selected, and m may be from 1 to 3. Claim 20, however, states only that “L² is” —P(R⁴)₃. It is therefore reasonably susceptible to different interpretations: that every L² is a phosphine ligand, that at least one L² is a phosphine ligand, or that an unidentified particular L² is a phosphine ligand. The specification separately uses “at least one L²” when describing a phosphine embodiment, confirming that the pending language does not clearly express the intended scope.
The claims may be clarified by amending claims 19 and 20 to depend from claim 18 and, with respect to claim 20, specifying whether at least one L² or each L² is —P(R⁴)₃.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), 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.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 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.
Claims 19-20 rejected under 35 U.S.C. 112(d) or pre-AIA 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.
Claims 19 and 20 are rejected under 35 U.S.C. § 112(d) as being of improper dependent form for failing to specify a further limitation of the subject matter of claim 1.
Claim 19 refers to claim 1 and then states that M is ruthenium. Claim 1 contains no element identified as M, and claim 19 does not state that M represents the metal of the transition metal-based catalyst. Consequently, the recitation concerning M does not further limit any identified element or step of claim 1.
Claim 20 refers to claim 1 and then limits L² to a phosphine structure. Claim 1 contains no element identified as L², no catalyst formula containing L², and no ligand requirement to which the added limitation can attach. The L² limitation therefore does not further limit any identified subject matter of claim 1. Claims in dependent form must incorporate the limitations of the referenced claim and then specify an ascertainable further limitation of that subject matter
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DEBORAH D CARR whose telephone number is (571)272-0637. The examiner can normally be reached Monday-Friday (10:30 am -6:30 pm).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Renee Claytor can be reached at 572-272-8394. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DEBORAH D CARR/ Primary Examiner, Art Unit 1691
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