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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 04/27/2026 has been entered.
Current Status
This action is responsive to the amended claims of 04/27/2026. Claim 1 is pending and has been amended. Claim 1 has been examined on the merits.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
The effective filing date remains 11/09/2016.
Response to Arguments
Examiner acknowledges receipt of and has reviewed the amendments, remarks, and declaration of 04/27/2026; no new matter is found.
The objection to the Drawings is withdrawn; the replacement sheets of 04/27/2026 improve resolution.
The objection to claim 1 regarding punctuation is maintained since the issue was not addressed by the amendments.
The objection to claim 1 regarding the structure of alpha yohimbine HCl is withdrawn since a corrected structure was provided.
The 101 rejection of claim 1 is maintained. Applicant’s arguments have been considered but are not persuasive.
1) Applicant argues the composition is markedly different since the mixture of indoles is not the same as that found in the Rauwolfia leaves and the compounds are formulated as salts. The salts having the same pharmaceutical properties as the corresponding free bases is irrelevant. The composition is markedly changed since the composition can be administered to humans – a property absent from the starting leaves – and the natural product cannot be formulated into a pill.
Examiner disagrees. First, the pharmaceutical properties being shared between free base and salts of yohimbine/alpha-yohimbine is a point towards no marked difference between the two forms (see argument 2) below for further discussion).
Second, the properties of “suitable for administration to humans” and “formulated into a pill” have not been proven by Applicant (by data, literatures, etc.) to be exclusive to the instant composition and not the naturally occurring Rauwolfia leaves. This constitutes Attorney arguments and cannot be considered evidence (see MPEP 2145(I)). In fact, it is known in the art that the leaves can be administered to humans in multiple forms including pill. IQBAL (Iqbal, A.A.M. et al., International Journal of Pharmaceutical and Phytopharmacological Research, 2013, 2(4), 247-251) discloses leaves of Rauwolfia tetraphylla are consumed to treat asthma by Kaani tribe in South India; a leaf and root paste is made into a pill to treat malarial fever by Bedar tribe of Karnataka; the Sholaga tribe uses leaf juice for headache and fever (Pg. 248 Left col. ¶3). Further, the instant claim does not require the composition is a pill. Thus, the properties which Applicant argues make the instant composition and the component indoles different from the leaves of Rauwolfia are not found markedly different.
2) Applicant argues the Myriad decision does not address what is meant by “marked” change.
Examiner does not find this persuasive. MPEP 2106.04(c)(II.)(B.) provides guidelines for the Markedly Different Characteristics Analysis: appropriate characteristics include biological and pharmacological functions or activities, chemical/physical properties, and structure. As discussed under argument 1), the biological and pharmacological functions of the compounds’ free bases and salt forms are the same (see Remarks of 02/27/2023 Pg. 1 Para 4). Both the salts and free bases (as found in the leaves of Rauwolfia) can be made into pharmaceutical compositions (e.g., pill) and administered to humans – the chemical/physical properties are not markedly different. As discussed previously in the rejection itself, the formation of a complex with a salt former (e.g., HCl) does not actually change the structure of the indole compounds yohimbine and alpha-yohimbine. Thus, the natural products claimed are not markedly different from their naturally occurring counterparts.
Mixing natural products, even at ratios different to those in the leaves, does not make the mixture any less natural. This would be akin to saying a salad is not a natural product since the components do not grow as a salad in a garden. Or that a portion of tea is not a natural product since the tea leaves do not grow as the liquid tea. As discussed, the characteristics used for the analysis do not point towards any marked difference.
Further, Examiner previously explained why the patentable cDNA of Myriad (Myriad, 569 U.S. at 595, 106 USPQ2d at 1981) is not equivalent to the instantly claimed composition (see the rejection below). Examiner maintains this position.
3) Applicant argues nothing in claim 1 could affect future study or use of yohimbine/alpha yohimbine unless such use fell within the narrowly defined claim.
Examiner does not find this persuasive. Even if the current claim is directed to a narrowly defined composition, a use of the natural products is still tied up.
The 103 rejection of claim 1 over MAURYA, KUMAR, LEONE, MILNE, and ANSEL is maintained. Applicant’s arguments have been considered but are not persuasive.
1) Applicant argues MAURYA provides no purity for the alpha yohimbine extract.
Examiner disagrees. As cited in the previous rejection, at least the abstract on Pg. 407 of MAURYA states “which afforded 160.4 mg of α-yohimbine (3) and 150.2 mg of reserpiline (4) in >95% purities.” The plural word “purities” applies this >95% to both reserpiline and α-yohimbine.
2) Applicant argues while various alkaloids were known to exist in Raowolfia leaves and there were known techniques for extracting such – none of the art shows a composition as claimed. The composition has the advantage of being easy and relatively cheap to produce while being suitable for administration to human for specific purposes – knowing what to include and what to exclude is the invention. The composition has the surprising property of being administrable to humans.
Examiner does not find this persuasive. As discussed above (¶10) and in the 103 rejection of 10/27/2025, the fact that the composition is suitable for human administration is not surprising and is not a “new” or “inventive” concept when compared to what is known in the art. Between MAURYA, KUMAR, and LEONE, it is well established that alpha-yohimbine, yohimbine, and Rauwolfia leaf/plant products are known to be suitable for human administration. This property is not surprising.
3) Applicant argues, even in view of ANSEL, this is not a case where the skilled worker can optimize by routine experimentation to achieve the instant result.
Examiner does not find this persuasive. Applicant has provided no data showing that the instant composition achieves some unexpected result or has critical characteristics which take advantage of the known properties of the compounds (see MPEP 716.02(a) & (d)). Statements from the Attorney merely positing that the instant composition cannot be achieved by routine optimization does not prove criticality of the claimed ranges nor a surprising result.
4) Applicant argues patent eligibility via Myriad.
Examiner does not find this persuasive. Patent eligibility is not considered in an obviousness-type prior art rejection. Further, this point was addressed in ¶10 argument 2), above.
5) Applicant Goel provided a declaration. Applicant states the impurities do not need to be listed in the claim since the nature of the Rauwolfia leaves defines the genus from which the impurities are chosen. Use of the leaves as the starting material leads to commercial success discussed previously. Nothing in the prior art teaches a composition of yohimbine HCl and alpha-yohimbine HCl.
Examiner does not find this persuasive. First, since the leaves define the genus of impurities this supports a broadest reasonable interpretation that any extract from the claimed Rauwolfia leaves having at least alpha-yohimbine and/or yohimbine can be applied as prior art. This does not exclude the art already applied.
Second, the “commercial success” has not been proven. As discussed in each of the previous actions, Applicant has not provided evidence that commercial success is due to the properties of the composition itself and not external factors. The declaration discussing commercial success, provided 08/08/2025, was of too low resolution to confidently read (see action of 10/27/2025 Pg. 6 ¶13). No supplemental or new evidence has been submitted with the reply of 04/27/2026.
Third, an anticipatory rejection is not made. While Examiner has not found art that anticipates the instant composition, based on the art applied previously and maintained below, the instant composition is obvious.
The double patenting rejection of claim 1 over co-pending App. no. 17/766,410 is maintained. Applicant did not address the merits of the rejection and asked the issue be deferred.
Response to RCE – Maintained Rejections
Claim Objections
Claim 1 is objected to because of the following informalities: the claim lacks commas between the recitation of each component of the composition. Please amend the claim as such: “obtained from the leaves of Rauwolfia Canescens, a detectable impurity of yohimbine hydrochloride, and 7-10% other alkaloids” (i.e., adding two commas where underlined). Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 1 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more. The claim recites a composition comprising 90-93% of solid hydrochloride of alpha yohimbine, a detectable impurity yohimbine hydrocholoride, and 7-10% other alkaloids, all of which are extracted from a plant, Rauwolfia Canescens, and are therefore found in nature. This judicial exception is not integrated into a practical application because the clause “wherein said composition is suitable for administration to humans” does no more than define a context in which the invention would operate. The “wherein” clause does not constitute the application of the judicial exception to affect a particular treatment or prophylaxis for a disease or medical condition. The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because the clause “hydrochloride” refers to a hydrochloride salt of alpha yohimbine/yohimbine and making the salt of a compound is a well-understood, routine, conventional activity in the art. Further, the concentration clauses “90-93%” and “7-10%” do not amount to significantly more since the separation and purification of a compound are also well-understood in the art.
Step 1: Is the claim drawn to a process, machine, manufacture, or composition of matter?
The broadest reasonable interpretation of the claim is drawn to a composition of matter, in this case, a composition comprising 90-93% of solid hydrochloride of alpha yohimbine, a detectable impurity yohimbine hydrocholoride, and 7-10% other alkaloids.
Revised Step 2A:
Prong One: Does the claim recite an abstract idea, law of nature, or natural phenomenon?
Yes, the broadest reasonable interpretation of the claim is drawn to a composition of natural products, in this case, a composition comprising 90-93% of solid hydrochloride of alpha yohimbine, a detectable impurity yohimbine hydrocholoride, and 7-10% other alkaloids, all of which are extracted from the plant Rauwolfia Canescens.
Claim 1 recites the alpha yohimbine with a detectable impurity yohimbine is “obtained from the leaves of Rauwolfia Canescens” and the other alkaloids are also “extracted from the leaves of Rauwolfia Canescens.” Thus, each one of the components of the composition is understood to be a product of nature (i.e., originating in a plant). Moreover, Examiner cites MAURYA (Maurya, A. et al., J. Sep. Sci., 2013, 36, 407-413, provided by Examiner 03/13/2025) as evidentiary reference. MAURYA discloses alpha-yohimbine is an indole alkaloid found in Rauwolfia Canescens (Pg. 407 Left Col. Para 1). Further, Examiner cites evidentiary reference KUMAR (Kumar, A. et al. J Chem. Pharm. Res., 2011, 3(2), 907-910) which discloses ten indole alkaloids – ajmaline, yohimbine, alpha-yohimbine, isoreserpine, corynanthine, deserpidine, reserpiline, isoreserpiline, aricine, and lankanescine have been isolated and identified from Rauwolfia Canescens (Pg. 908 para 2). Thus, alpha yohimbine and yohimbine are understood to be naturally occurring compounds, i.e., products of nature. Since the Applicant did not define the identity of the “other alkaloids,” at least 8 other alkaloids are known in Rauwolfia Canescens, and since the claim states the other alkaloids are extracted from Rauwolfia Canescens, the other alkaloids are also understood to be naturally occurring compounds, i.e., products of nature. Furthermore, since all 3 components are found in the plant Rauwolfia Canescens, the combination of the components into a composition does not have any additive power that, when viewed as a whole, the composition is not nature-based.
Regarding the alpha yohimbine and yohimbine both being in the hydrochloride salt form, see MPEP 2106.04(c): “In Myriad, the Supreme Court made clear that not all changes in characteristics will rise to the level of a marked difference, e.g., the incidental changes resulting from isolation of a gene sequence are not enough to make the isolated gene markedly different. Myriad, 569 U.S. at 580, 106 USPQ2d at 1974-75. The patentee in Myriad had discovered the location of the BRCA1 and BRCA2 genes in the human genome, and isolated them, i.e., separated those specific genes from the rest of the chromosome on which they exist in nature. As a result of their isolation, the isolated genes had a different structural characteristic than the natural genes, i.e., the natural genes had covalent bonds on their ends that connected them to the rest of the chromosome, but the isolated genes lacked these bonds. However, the claimed genes were otherwise structurally identical to the natural genes, e.g., they had the same genetic structure and nucleotide sequence as the BRCA genes in nature. The Supreme Court concluded that these isolated but otherwise unchanged genes were not eligible, because they were not different enough from what exists in nature to avoid improperly tying up the future use and study of the naturally occurring BRCA genes. See, e.g., Myriad, 569 U.S. at 585, 106 USPQ2d at 1977”.
In the instant case, the hydrochloride of alpha yohimbine has one small structural difference to the naturally occurring alpha yohimbine, i.e., it is associated with an HCl:
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. Otherwise, the two chemical compounds are structurally identical. The same is true for the yohimbine hydrochloride and yohimbine. This small structural difference, i.e., association with HCl, can be viewed as an incidental change resulting from isolation of the alpha yohimbine and yohimbine from the source plant. Further, Applicant admits (see Remarks of 02/27/2023 Pg. 1 Para 4) that alpha yohimbine and its hydrochloride salt have the same biological properties. Thus, the solid hydrochloride of alpha yohimbine and hydrochloride yohimbine are not found to be markedly different from the naturally occurring free-base counterparts.
The same analysis applies to the limitations “90-93%” alpha yohimbine and “7-10%” other alkaloids. The composition comprising 90-93% alpha yohimbine hydrochloride and 7-10% other alkaloids all obtained/extracted from the leaves of Rauwolfia Canescens is an incidental change that results from the isolation of the alpha yohimbine and alkaloids from the plant source. Just because the claimed composition has relatively more or less of each component does not change the structural or chemical properties of the natural products.
Further note, the patentable cDNA of Myriad (Myriad, 569 U.S. at 595, 106 USPQ2d at 1981) is not equivalent to the instantly claimed composition.
In the instant case, there is no structural difference in the claimed alpha yohimbine vs. alpha yohimbine in the leaf; the same is said for yohimbine and the other alkaloids. While alpha yohimbine and yohimbine are in the hydrochloride salt form, the fundamental structure of the alkaloid itself has not been changed. A mere association with a salt former (HCl) does not change the bonding and/or atoms contained within the yohimbine structures. In the case of Myriad, the introns were missing from the patentable cDNA, thus, the structure had been fundamentally changed from naturally occurring DNA. This would be more equivalent to a change in the bonding and/or atoms within the chemical structures of the yohimbine alkaloids. Since the underlying yohimbine alkaloid structures are the same as their naturally occurring counterparts, the hydrochloride salt forms are understood as natural products.
Hence, the rejected claim is drawn to a judicial exception (JE).
Prong Two: Does the Claim Recite Additional Elements that Integrate the Judicial Exception (JE) into a Practical Application?
No.
Claim 1 recites three additional elements. The first is the “solid hydrochloride” of alpha yohimbine and the “hydrochloride” of yohimbine. This element does not integrate the JE into a practical application since it merely describes the physical form of the compounds. The second additional element is the concentration limitations “90-93%” alpha yohimbine hydrochloride and “7-10%” other alkaloids. The second element, similarly, does not integrate the JE into a practical application since it merely describes a chemical property of the composition (i.e., concentration of components). The third additional element is the clause “wherein said composition is suitable for administration to humans.” This “wherein” clause suggests a field of use in which the invention would operate, i.e., in a setting where the compound is administered to a human. However, the “wherein” clause does not constitute the application of the JE to a practical application, such as, affecting a particular treatment or prophylaxis for a disease/medical condition since the clause does not recite an administration step.
Further these elements, together, do not integrate the JE into a practical application for the same reasons as stated above. The additional elements do not have any additive power, where together they define a practical application. At most, a field of use is suggested, e.g., human medicine. However, no positive steps are recited within claim 1 and, so, the additional elements do not integrate the JE into a practical application.
See also MPEP 2106.04(d)(2)(a) and (c) regarding a discussion of the particularity of treatment/prophylaxis and why a ‘field of use’ limitation fails to integrate a JE into a practical application.
Step 2B: Does the claim recite additional elements that amount to significantly more than the JE?
No.
Regarding the first additional element, the synthesis of salt forms of compounds, including hydrochloride solids, is well-understood, routine, and conventional in the art. BOWKER (Bowker, Michael J., Handbook of Pharmaceutical Salts Properties, Selection, and Use: Chapter 7, edited by Heinrich P. Stahl and Camille G. Wermuth, Wiley-VCH, Weinheim, Germany, 2002, pp. 161–189, provided by Examiner 03/13/2025) discloses a process of salt selection and optimization for formation of salt forms of compounds, summarized in the Figure on Pg. 165. BOWKER provides strategies for choosing the salt former counter-ion (Pg. 167-168 Section 3.1) and recites hydrochloride as a common pharmaceutical salt former (Pg. 168 Table 1). BOWKER also provides strategies for scaling up the preparation of salts (Pg. 168-170 Section 3.2) and suggests studies for comparison of the chosen salt form and the parent compound for oral dosage forms (Pg. 171 Table 2). Thus, the synthesis of salt forms, including hydrochloride, is well-understood in the art and is a routine and conventional practice. Therefore, the salt form “hydrochloride” of alpha yohimbine and yohimbine does not amount to significantly more than the JE, i.e., the natural products alpha yohimbine and yohimbine.
Regarding the second additional element, the separation of alpha-yohimbine, yohimbine, and other alkaloids from plant materials, including Rauwolfia canescens, and purification of alpha-yohimbine to at least 90% is well-understood, routine, and conventional in the art.
MAURYA (Maurya, A. et al., J. Sep. Sci., 2013, 36, 407-413, provided by Examiner 03/13/2025) discloses a method for large-scale separation of alkaloids from Rauwolfia Tetraphylla (Pg. 407 Title). Note, Rauwolfia Tetraphylla is a synonym for Rauwolfia Canescens (Pg. 407 Introduction Line 1). MAURYA discloses pH-zone-refining centrifugal partition chromatography was successively applied in the large-scale separation of four indole alkaloids directly from fractions of Rauwolfia Tetraphylla leaves: 10-methoxytetrahydroalstonine, isoreserpiline, alpha-yohimbine, and reserpiline (Pg. 407 Abstract). The method afforded alpha-yohimbine of >95% purity (Pg. 407 Abstract); i.e., ~5% other alkaloids.
GUPTA (Gupta, S. et al., Journal of Pharmaceutical and Biomedical Analysis, 2012, 66, 33-39, provided by Examiner 03/13/2025) discloses an HPTLC method for the quantitation of four antipsychotic indole alkaloids in the leaves of Rauwolfia Tetraphylla: 10-methoxytetrahydroalstonine, isoreserpiline, alpha-yohimbine, and reserpiline (Pg. 33 Abstract). The method includes the extraction and isolation of the indole alkaloids from Rauwolfia Tetraphylla leaves (Pg. 34 Section 2.4 & Pg. 36 Section 3.1). The HPTLC method measured the purity of the extracted alpha-yohimbine sample at 98% (Pg. 38 Table 2); i.e., 2% other alkaloids.
KUMAR (Kumar, A. et al. J Chem. Pharm. Res., 2011, 3(2), 907-910) discloses ten indole alkaloids – ajmaline, yohimbine, alpha-yohimbine, isoreserpine, corynanthine, deserpidine, reserpiline, isoreserpiline, aricine, and lankanescine have been isolated and identified from Rauwolfia Canescens (Pg. 908 para 2). Further, KUMAR discloses a method for the extraction, isolation, identification, and quantitative determination of the alkaloid yohimbine in the leaves of Rauwolfia Tetraphylla (Pg. 908 para 3 & Pg. 908-909 Experimental Sect.); 6.11% of yohimbine was present in the leaves of Rauwolfia Tetraphylla (Pg. 909 para 7), i.e., ~93% other alkaloids such as alpha yohimbine.
Thus, Examiner relies upon MAURYA, GUPTA, and KUMAR to demonstrate that the separation of alpha yohimbine, yohimbine, and other alkaloids from Rauwolfia Canescens leaves, is well-understood in the art and is a routine and conventional practice. Therefore, a composition comprising 90-93% alpha yohimbine, an impurity yohimbine, and 7-10% other alkaloids does not amount to more than the JE, i.e., the natural products alpha yohimbine, yohimbine, and other Rauwolfia alkaloids.
Regarding the third additional element, the clause “wherein said composition is suitable for administration to humans” is considered to generally link the judicial exception to a particular field of use. However, the “wherein” clause does not constitute the application of the JE to a practical application (as discussed in Step 2A Prong 2). Thus, the “wherein” clause is merely a field of use limitation which does not amount to an inventive concept.
Further, while the claim does not positively recite an administration step, the administration of alpha-yohimbine and its hydrochloride salt is well-understood, routine, and conventional in the art.
MAURYA (Maurya, A. et al., J. Sep. Sci., 2013, 36, 407-413, provided by Examiner 03/13/2025) discloses alpha-yohimbine is used for treating neurodegenerative disease and neurotoxicity in Alzheimer’s disease and it has shown stimulant, aphrodisiac, and antiviral activities (Pg. 407 Right Col. Para 2); aricine/10-methoxytetrahydroalstonine has been used as bactericide and fungicide and isoreserpiline possesses antidiabetic activity (Pg. 407 Right Col. para 2). Thus, Rauwolfia alkaloids have many known uses in the field of pharmacology.
MILNE (WO 2010/148519, provided by Examiner 03/13/2025) discloses a method for alleviating or delaying onset of pain in a subject comprising administering rauwolscine hydrochloride (i.e., alpha yohimbine hydrochloride) (Pg. 38 Claims 1-2) to humans (Pg. 24 Lines 16-20). Thus, alpha-yohimbine hydrochloride is suitable for administration to humans.
LEONE (EP 1086695, provided by Examiner 03/13/2025) discloses yohimbine in all its isomeric forms possesses effective antiviral properties (Pg. 2 Col. 1 Lines 51-53). LEONE further teaches a woman (i.e., a human) was treated with a composition comprising yohimbine HCl in the form of a tablet, i.e., a solid form (Pg. 3 Col. 4 Para 22). Thus, yohimbine hydrochloride is suitable for human administration.
Thus, the administration of alpha yohimbine hydrochloride, yohimbine hydrochloride, and other alkaloids extracted from Rauwolfia, is well-understood in the art and is a routine and conventional practice. Therefore, the “wherein” clause does not amount to significantly more than the JE.
Thus, claim 1 is rejected under 35 USC 101.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over:
MAURYA (Maurya, A. et al., J. Sep. Sci., 2013, 36, 407-413, provided by Examiner 03/13/2025), in view of
KUMAR (Kumar, A. et al. J Chem. Pharm. Res., 2011, 3(2), 907-910), in view of
LEONE (EP 1086695, provided by Examiner 03/13/2025), in view of
MILNE (WO 2010/148519, provided by Examiner 03/13/2025), and in view of
ANSEL (Ansel, H.C. et al. Pharmaceutical Dosage Forms and Drug Delivery Systems, Lippincott Williams & Wilkins, 7th ed., 1999, pages 48-53).
Determining the Scope and Contents of the Prior Art:
MAURYA teaches the large-scale separation of indole alkaloids directly from fractions of Rauwolfia Tetraphylla leaves (Pg. 407 Abstract), i.e., Rauwolfia Canescens (Pg. 407 Introduction Line 1). MAURYA teaches a system was optimized for the preparative separation and purification of four antipsychotic indole alkaloids, including alpha-yohimbine (Pg. 408 Right Col. Para 2 & Fig. 1). MAURYA teaches a mixture comprising alpha-yohimbine, separated from the crude leaf extract, was resolved over medium-pressure LC and the eluted fractions resulted in the isolation of alpha-yohimbine in 95% purity (Pg. 411 Left Col. Para 2 and Fig 4E; Pg. 407 Abstract). MAURYA further teaches conventional methods for separation and purification of alkaloids from plant materials are tedious and result in low recovery of bioactive molecules; however, the method utilized by MAURYA provides increased sample-loading capacity (i.e., increased efficiency), high purity and concentration, and minor impurities (Pg. 408 Left Col. Para 2). MAURYA also teaches Rauwolfia Canescens is an important medicinal plant cultivated on commercial scale (Pg. 407 Left Col. Para 1); further, alpha-yohimbine is used for treating neurodegenerative disease and neurotoxicity in Alzheimer’s disease and has shown stimulant, aphrodisiac, and antiviral activities (Pg. 407 Right Col. Para 2).
KUMAR discloses ten indole alkaloids – ajmaline, yohimbine, alpha-yohimbine, isoreserpine, corynanthine, deserpidine, reserpiline, isoreserpiline, aricine, and lankanescine have been isolated and identified from Rauwolfia Canescens (Pg. 908 para 2). Further, KUMAR discloses a method for the extraction, isolation, identification, and quantitative determination of the alkaloid yohimbine in the leaves of Rauwolfia Tetraphylla (Pg. 908 para 3 & Pg. 908-909 Experimental Sect.); 6.11% of yohimbine was present in the leaves of Rauwolfia Tetraphylla (Pg. 909 para 7), i.e., ~93% other alkaloids such as alpha yohimbine.
LEONE teaches yohimbine in all its isomeric forms, and in particular alpha-yohimbine, possesses effective antiviral properties (Pg. 2 Col. 1 Lines 51-53). LEONE further teaches the use of yohimbine salts, in particular yohimbine hydrochloride, to produce pharmaceutical compositions having antiviral activity (Pg. 2 Col. 2 Lines 1-4). LEONE further teaches a woman (i.e., a human) was treated with a composition comprising yohimbine HCl in the form of a tablet, i.e., a solid form (Pg. 3 Col. 4 Para 22).
MILNE teaches a method for alleviating or delaying onset of pain in a subject comprising administering rauwolscine hydrochloride (i.e., alpha yohimbine hydrochloride) (Pg. 38 Claims 1-2). MILNE teaches the subject being administered the rauwolscine hydrochloride includes humans (Pg. 24 Lines 16-20). MILNE further teaches solid dosage forms (Pg. 28 Lines 8-11).
ANSEL teaches the safe and effective dose of a drug depends on a number of
factors including characteristics of the drug, the dosage form, and a variety of patient
factors (Pg. 48 Left Col. para 2) and the effective dose may be different for different
patients (Pg. 48 Left Col. para 4).
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
MAURYA does not teach the alpha yohimbine is in a composition at 90-93% as the solid hydrochloride, and does not explicitly state that the alpha yohimbine is suitable for human administration.
KUMAR does not teach a composition comprising the instant concentrations of the claimed components.
LEONE and MILNE do not teach the yohimbine/alpha-yohimbine hydrochloride is extracted from Rauwolfia Canescens or is at the instant concentration.
ANSEL does not teach the instant composition.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of a composition comprising Rauwolfia Canescens alkaloids useful for administration to humans and possesses the technical knowledge necessary to make adjustments to the composition and extraction process of the alkaloids from plant matter to optimize/enhance the resulting product for medicinal use. Said artisan has also reviewed the problems in the art regarding the extraction/separation and use of said alkaloids and understands the solutions that are widely-known in the art.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
The instant claim is prima facie obvious in light of the combination of references MAURYA, in view of KUMAR, in view of LEONE, in view of MILNE, and in view of ANSEL.
The artisan would find it obvious to utilize the separation process taught by MAURYA to extract highly pure alpha-yohimbine. The artisan would be motivated to utilize MAURYA’s separation process since the process is an improvement upon traditional methods (Pg. 408 Left Col. Para 2) and produces alpha-yohimbine of ~95% purity (Pg. 411 Left Col. Para 2, Pg. 407 Abstract). Based on the teachings of KUMAR (Pg. 908 para 2), the artisan would recognize that the other ~5% of the extract of MAURYA would comprise other Rauwolfia Canescens alkaloids including yohimbine.
The artisan would further find it obvious to form the hydrochloride salts of both alpha-yohimbine and yohimbine to form a solid pharmaceutical composition. The artisan would be motivated, with an expectation of success, to form the hydrochloride solid of the alpha-yohimbine since MILNE teaches administration of alpha-yohimbine hydrochloride to a human subject (Pg. 38 Claims 1-2, Pg. 24 Lines 16-20). The artisan would have further motivation since LEONE teaches that yohimbine and alpha-yohimbine are medicinally effective (Pg. 2 Col. 1 Lines 51-53), the HCl salt is the preferred form for pharmaceutical compositions (Pg. 2 Col. 2 Lines 1-4), and are suitable for administration to humans (Pg. 3 Col. 4 Para 22).
Since both LEONE (Pg. 3 Col. 4 Para 22) and MILNE (Pg. 28 Lines 8-11) teach preferred solid dosage forms of yohimbine/alpha-yohimbine hydrochloride for human administration, and since LEONE teaches yohimbine and alpha-yohimbine are medicinally effective (Pg. 2 Col. 1 Lines 51-53), the artisan would be motivated to form a composition comprising both alpha-yohimbine and yohimbine hydrochloride for use in humans. The artisan would be further motivated to create the composition from MAURYA’s extract since MAURYA teaches a method with improved efficiency and minor impurities (Pg. 408 Left Col. Para 2). The artisan would have an expectation of success in creating a human-suitable composition from the extract of MAURYA, which is understood to contain a majority alpha-yohimbine and a minority yohimbine (in view of KUMAR), in view of the dosage forms taught in LEONE and MILNE. Furthermore, since MAURYA teaches Rauwolfia Canescens is an important medicinal plant (Pg. 407 Left Col. Para 1) and alpha-yohimbine has various pharmacological uses (Pg. 407 Right Col. Para 2), the artisan would understand MAURYA to contain an indication that the extraction protocol taught within is useful for development of alpha-yohimbine-containing pharmaceuticals.
Regarding the limitations “90-93%” alpha-yohimbine hydrochloride and “7-10%” other alkaloids, the artisan would have been motivated to optimize the concentrations of the alpha-yohimbine and other alkaloids in the composition. MPEP 2144.05(II)(A) provides guidance about the routine optimization of prior art conditions: "Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.").”
Furthermore, MPEP 2144.05(I) provides guidance about overlapping and approaching ranges: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists…Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close.”
In the instant case, MAURYA teaches an extract of alpha-yohimbine with ~95% purity (Pg. 411 Left Col. Para 2 and Fig 4E; Pg. 407 Abstract). In view of KUMAR (Pg. 908 para 2), the other ~5% of the extract would be understood to contain other Rauwolfia alkaloids including yohimbine. These percentages approach the instantly claimed “90-93%” alpha-yohimbine hydrochloride and “7-10%” other alkaloids. Since ANSEL teaches the safe and effective dose of a drug depends on drug characteristics, the dosage form, and a variety of patient factors (Pg. 48 Left Col. para 2) and the effective dose may be different for different patients (Pg. 48 Left Col. para 4), the artisan would recognize the dosage of alpha-yohimbine and other alkaloids as a variable for optimization. The concentration of the alpha-yohimbine and other alkaloids (90-93% and 7-10%) within the composition is understood by Examiner to be equivalent to the dose suitable for human administration. Thus, the artisan would recognize the concentrations of alpha-yohimbine and the other alkaloids as a result-effective variable, i.e., a variable that achieves a recognized result. Furthermore, the MPEP sections above recite wherein “concentration” may be optimized by routine experimentation. Absent any evidence demonstrating the criticality of the claimed concentrations (see MPEP 716.02), the determination of the optimum or workable concentrations would have been generally prima facie obvious to the artisan.
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 provisionally rejected on the ground of obviousness-type nonstatutory double patenting as being unpatentable over claim 4 of co-pending Application No. 17/766,410 (claims of 02/13/2026) in view of MAURYA (Maurya, A. et al., J. Sep. Sci., 2013, 36, 407-413, provided by Examiner 03/13/2025), in view of KUMAR (Kumar, A. et al. J Chem. Pharm. Res., 2011, 3(2), 907-910), in view of LEONE (EP 1086695, provided by Examiner 03/13/2025), in view of MILNE (WO 2010/148519, provided by Examiner 03/13/2025), and in view of ANSEL (Ansel, H.C. et al. Pharmaceutical Dosage Forms and Drug Delivery Systems, Lippincott Williams & Wilkins, 7th ed., 1999, pages 48-53).
Determining the Scope and Contents of the Prior Art:
Claim 4 of App. No. ‘410 is drawn to an extract comprising a precipitate of alpha yohimbine hydrochloride and yohimbine hydrochloride in analytically detectable amount of more than 0.1% of the extract. Claim 4 is drawn to the product of the process of making recited in claim 1. Claim 1 recites wherein leaves of a Rauwolfia plant species are processed to form an extract wherein the last two steps comprise adding hydrochloric acid and drying the final precipitate of alpha yohimbine. Examiner understands, based on these last two steps, that the alpha yohimbine is in the solid hydrochloride form. Thus, claim 4 is drawn to a composition comprising solid alpha-yohimbine hydrochloride and at least 0.1% yohimbine hydrochloride.
The teachings of MAURYA, KUMAR, LEONE, MILNE, and ANSEL are above, ¶20.
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
The claim of App. No. ‘410 does not teach wherein the composition comprises alpha-yohimbine at 90-93% and 7-10% other alkaloids, nor where the composition is suitable for human administration.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of a composition comprising Rauwolfia Canescens alkaloids useful for administration to humans and possesses the technical knowledge necessary to make adjustments to the composition and extraction process of the alkaloids from plant matter to optimize/enhance the resulting product for medicinal use. Said artisan has also reviewed the problems in the art regarding the extraction/separation and use of said alkaloids and understands the solutions that are widely-known in the art.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
The instant claims are prima facie obvious in light of the combination of references App. No. ‘410, in view of MAURYA, in view of KUMAR, in view of LEONE, in view of MILNE, and in view of ANSEL.
The composition of App. No. ‘410 and the extract of MAURYA are analogous – both contain alpha-yohimbine extracted from Rauwolfia species. Further, in view of KUMAR (Pg. 908 para 2), the artisan would recognize that both the composition of App. No. ‘410 and the extract of MAURYA would comprise other Rauwolfia alkaloids. Since the composition of App. No. ‘410 and the extract of MAURYA are analogous, the same logic laid out in the above 103 rejection would apply here. In short, MAURYA’s extract contains ~95% alpha-yohimbine and ~5% other alkaloids. Thus, the reference composition would be understood to contain x% of alpha-yohimbine hydrochloride and y% of other alkaloids wherein y% comprises at least 0.1% yohimbine hydrochloride.
Since both LEONE (Pg. 3 Col. 4 Para 22) and MILNE (Pg. 28 Lines 8-11) teach preferred solid dosage forms of yohimbine/alpha-yohimbine hydrochloride for human administration, and since LEONE teaches yohimbine and alpha-yohimbine are medicinally effective (Pg. 2 Col. 1 Lines 51-53), the artisan would be motivated to form a composition comprising both alpha-yohimbine and yohimbine hydrochloride to administer to humans. Furthermore, since MAURYA teaches Rauwolfia Canescens is an important medicinal plant cultivated on commercial scale (Pg. 407 Left Col. Para 1) and extraction of alpha-yohimbine from Rauwolfia Canescens (Pg. 411 Left Col. Para 2 and Fig 4E; Pg. 407 Abstract), the artisan would be motivated to utilize Rauwolfia Canescens as the species of Rauwolfia plant in reference claim 4.
Regarding the instant limitations “90-93%” alpha-yohimbine hydrochloride and “7-10%” other alkaloids, the artisan would have been motivated to optimize the concentrations of the alpha-yohimbine and other alkaloids in the composition. MPEP 2144.05(II)(A) and MPEP 2144.05(I) provides guidance about the routine optimization of prior art conditions (see ¶20, above).
In the instant case, MAURYA teaches an extract of alpha-yohimbine with 95% purity (Pg. 411 Left Col. Para 2 and Fig 4E; Pg. 407 Abstract). In view of KUMAR (Pg. 908 para 2), the other 5% of the extract would be understood to contain other Rauwolfia alkaloids including yohimbine. These percentages approach with the instantly claimed “90-93%” alpha-yohimbine hydrochloride and “7-10%” other alkaloids and the reference claims 4 teachings of at least 0.1% yohimbine. Since ANSEL teaches the safe and effective dose of a drug depends on drug characteristics, the dosage form, and a variety of patient factors (Pg. 48 Left Col. para 2) and the effective dose may be different for different patients (Pg. 48 Left Col. para 4), the artisan would recognize the dosage of alpha-yohimbine and other alkaloids as a variable for optimization. The concentration of the alpha-yohimbine and other alkaloids (90-93% and 7-10%) within the composition is understood by Examiner to be equivalent to the dose suitable for human administration. Thus, the artisan would recognize the concentrations of alpha-yohimbine and the other alkaloids as a result-effective variable, i.e., a variable that achieves a recognized result. Furthermore, the MPEP sections above recite wherein “concentration” may be optimized by routine experimentation.
Since MAURYA is a prior art equivalent to the reference claims (based on their similar products), the artisan would view MAURYA’s reported concentrations as viable starting points for optimization of the concentration of the components in the reference claim composition. Thus, the determination of the optimum or workable concentrations of alpha-yohimbine and other alkaloids would have been well within the practice of the artisan. Absent any evidence demonstrating the criticality of the claimed concentrations, the determination of the optimum or workable concentrations would have been generally obvious to the artisan.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Claim 1 is rejected.
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/S.E.B./
Examiner, Art Unit 1625
/JOHN S KENYON/Primary Patent Examiner, Art Unit 1625
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