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 .
Current Status
This action is responsive to the amended claims of 08/08/2025. 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.
Drawings - Maintained
The drawings are objected to because Figures 1 & 3 are of low resolution. Please replace the images in the figures with higher quality images. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Response to Arguments
Examiner acknowledges receipt of and has reviewed the amendments, remarks, and declaration of 08/08/2025, no new matter is found.
The objection to the Drawings is maintained in part (above). The newly provided Figure 2 is of higher resolution; however, Figures 1 and 3 are still low resolution.
The objections to the specification are withdrawn since the Applicant has amended the specification in line with the Examiner’s suggestions.
The objections to claim 1 are withdrawn since the Applicant has provided a higher quality chemical structure and corrected the claim status and markup.
The 112b rejections of claim 1 is withdrawn because the Applicant has amended the claim to recite a composition and a chemical structure comprising the associated HCl. Thus, it is clear that claim 1 is drawn to a composition comprising 90-93% solid alpha-yohimbine hydrochloride.
The 101 rejection of claim 1 has been modified to account for Applicant’s amendments (see below). Applicant's arguments filed 08/08/2025 have been fully considered but they are not persuasive. Applicant argues that the instant composition is materially changed from the natural products found in the starting leaves and, thus, the situation is different from that of Myriad. Further, Applicant states no purity was indicated for alpha yohimbine in the teachings of MAURYA. Examiner respectfully disagrees, as previously cited, MAURYA teaches the method afforded alpha-yohimbine and reserpiline in >95% purities (Pg. 407 Abstract). Thus, MAURYA clearly teaches >95% purity of alpha-yohimbine.
Applicant argues that the presently claimed composition is more akin to the patent eligible cDNA of Myriad since the composition contains multiple compounds including alpha yohimbine. Examiner respectfully disagrees. In Myriad, the Supreme Court identified a claimed full-length complementary DNA (cDNA) of the BRCA1 gene as a nature-based product having markedly different characteristics. This claimed cDNA had the same functional characteristics (i.e., it encoded the same protein) as the naturally occurring gene, but had a changed structural characteristic, i.e., a different nucleotide sequence containing only exons, as compared to the naturally occurring sequence containing both exons and introns. The Supreme Court concluded that the "cDNA retains the naturally occurring exons of DNA, but it is distinct from the DNA from which it was derived. As a result, [this] cDNA is not a ‘product of nature’" and is eligible. Myriad, 569 U.S. at 595, 106 USPQ2d at 1981.
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/removed from the patent eligible 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. Thus, this line of argumentation is not found persuasive.
Applicant also states that forming a hydrochloride from a mixture comprising 90-93% alpha yohimbine cannot be regarded as a conventional step when it results in a product having the surprising property of being administrable to humans. Examiner respectfully disagrees that the property of being administrable to humans is surprising. As previously cited, MILNE (Pg. 24 Lines 16-20), and LEONE (Pg. 3 Col. 4 Para 22) each disclose the administration of alpha-yohimbine, yohimbine, and hydrochloride salts thereof to humans. Thus, it was known in the art that alpha yohimbine hydrochloride can be administered to humans. Finally, Applicants admit (see Remarks of 02/27/2023 Pg. 1 Para 4) that alpha yohimbine and its hydrochloride salt have the same biological properties and consequently they would be expected by the artisan to be equally suitable for administration to humans.
Furthermore, unexpected (i.e., surprising) results are not a consideration under patent subject matter eligibility (MPEP 2106), but are considered under evidence of non-obviousness (MPEP 716.02). Moreover, attorney arguments of surprising results cannot be considered evidence (see MPEP 2145(I)).
Applicant repeatedly stresses that what was not known was that a product having high content of alpha yohimbine could be administered to humans. However, Examiner would stress that the pending claim 1 does not integrate the judicial exception (composition comprising products of nature) into a practical application, such as administration to humans. The claim does not recite any positive steps which would affect a particular treatment or prophylaxis for a disease or medical condition in a human (see rejection below for further detail). Thus, this line of argumentation is not found persuasive.
The 102 rejection of claim 1 as anticipated by MAURYA is withdrawn due to Applicant’s amendments. Claim 1 is now clearly drawn to the HCl salt of alpha-yohimbine at a concentration of 90-93% in a composition. The reference MAURYA does not teach the HCl salt nor the concentration 90-93%.
The 103 rejection of claim 1 has been modified to account for Applicant’s amendments (see below). Applicant's arguments filed 08/08/2025 have been fully considered but they are not persuasive. Applicant argues that the difference between the combined prior art references and the instant claim is that the claimed invention takes advantage of the medicinal properties of alpha yohimbine in an efficient way that was not known in the art. Further, Applicant has provided a declaration concerning commercial success. Unfortunately, the declaration submitted on 08/08/2025 is of very poor resolution (i.e., faint and fuzzy text & graph) making it impossible to read the contents with confidence. Thus, the Examiner is unable to take the statements made within the declaration into account. Therefore, the argument for commercial success is only put forth in the attorney arguments which cannot be considered evidence (see MPEP 2145(I)). Since no other arguments are put forth as to how the instant claim takes advantage of the medicinal properties in an efficient way, the remarks against obviousness are not found persuasive.
New Objections
Claim Objections – Necessitated by Amendment
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 1 is further objected to regarding the recited chemical structure:
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the annotated carbon-carbon bonds are not properly connected in the structure. Based on the recitation “alpha yohimbine of the formula,” it is clear this structure is meant to be that of alpha yohimbine. However, since the formula is technically incorrect at the annotations, Applicant is advised to provide a corrected structure.
New Rejections
Claim Rejections - 35 USC § 101 – Necessitated by Amendment
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. Based on the claim language and knowledge in the art, one would expect to find a combination of the claimed alkaloids in nature, e.g., in the leaves of Rauwolfia Canescens.
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., e.g., they have the same chemical structure. 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, Applicants admit (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 alpha yohimbine.
The same analysis can be done regarding 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 each component.
Similar to Myriad where the court held “Myriad's patents would, if valid, give it the exclusive right to isolate an individual’s BRCA1 and BRCA2 genes … But isolation is necessary to conduct genetic testing," isolation of alpha yohimbine, yohimbine, and other alkaloids from the plant source is necessary to use the compounds for any purpose. Thus, a patent covering the currently claimed product would improperly tie up the future use and study of the naturally occurring alpha yohimbine, yohimbine, and other Rauwolfia Canescens alkaloids.
Further note, as stated above in response to Applicant’s arguments, 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.
Regarding the recitation of additional elements by the language of claim 1, it is noted that there are three additional elements. The first additional element is the “solid hydrochloride” of alpha yohimbine and the “hydrochloride” of yohimbine. The first element recites the compounds alpha yohimbine and yohimbine are in the form of a solid HCl salt; however, 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; the field of use being a medical setting where a human is administered the compound. 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. Examiner cites 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) as an evidentiary reference on the synthesis of pharmaceutical salts.
BOWKER 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 further 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, Examiner relies upon BOWKER to demonstrate that the synthesis of salt forms, including hydrochloride, has been well-understood in the art since, at least, 2002 and therefore 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. Examiner cites MAURYA (Maurya, A. et al., J. Sep. Sci., 2013, 36, 407-413, provided by Examiner 03/13/2025), GUPTA (Gupta, S. et al., Journal of Pharmaceutical and Biomedical Analysis, 2012, 66, 33-39, provided by Examiner 03/13/2025), and KUMAR (Kumar, A. et al. J Chem. Pharm. Res., 2011, 3(2), 907-910) as evidentiary references.
MAURYA 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). MAURYA discloses 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), 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). GUPTA discloses a method for the extraction and isolation of the indole alkaloids from Rauwolfia Tetraphylla leaves (Pg. 34 Section 2.4 & Pg. 36 Section 3.1) and states the obtained extracts were used in the HPTLC analysis (Pg. 36 Right Col. Para 2). GUPTA discloses the HPTLC method measured the purity of the extracted alpha-yohimbine sample at 98% (Pg. 38 Table 2); i.e., 2% other alkaloids.
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.
Thus, Examiner relies upon MAURYA, GUPTA, and KUMAR to demonstrate that the separation of alpha yohimbine, yohimbine, and other alkaloids from Rauwolfia Canescens leaves, has been well-understood in the art since, at least, 2012 and therefore 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 use in a particular field of use. Here, the suggested field of use is a pharmacological 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 (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. Examiner cites MAURYA (Maurya, A. et al., J. Sep. Sci., 2013, 36, 407-413, provided by Examiner 03/13/2025), MILNE (WO 2010/148519, provided by Examiner 03/13/2025), and LEONE (EP 1086695, provided by Examiner 03/13/2025) as evidentiary references.
MAURYA 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, MAURYA establishes Rauwolfia alkaloids have many known uses in the field of pharmacology.
MILNE 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). MILNE discloses administration to humans (Pg. 24 Lines 16-20). Thus, MILNE establishes alpha-yohimbine hydrochloride is suitable for administration to humans.
LEONE 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, LEONE establishes yohimbine hydrochloride is suitable for administration to humans.
Thus, Examiner relies upon MAURYA, MILNE, and LEONE to demonstrate that the administration of alpha yohimbine hydrochloride, yohimbine hydrochloride, and other Rauwolfia alkaloids, has been 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 – Necessitated by Amendment
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), KUMAR (Kumar, A. et al. J Chem. Pharm. Res., 2011, 3(2), 907-910), LEONE (EP 1086695, provided by Examiner 03/13/2025), MILNE (WO 2010/148519, provided by Examiner 03/13/2025), and 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 in order 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, KUMAR, LEONE, MILNE, and 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). 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 in order 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 with 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. 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. Furthermore, 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.
Together, MAURYA, KUMAR, LEONE, MILNE, and ANSEL teach claim 1.
Double Patenting – Necessitated by Amendment
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 07/01/2025) in view of MAURYA (Maurya, A. et al., J. Sep. Sci., 2013, 36, 407-413, provided by Examiner 03/13/2025), KUMAR (Kumar, A. et al. J Chem. Pharm. Res., 2011, 3(2), 907-910), LEONE (EP 1086695, provided by Examiner 03/13/2025), MILNE (WO 2010/148519, provided by Examiner 03/13/2025), and 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, paragraph 22.
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 in order 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, MAURYA, KUMAR, LEONE, MILNE, and 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 paragraph 22, 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 opt