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 .
This is a Non-Final office action.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 March 24, 2026 has been entered.
Election/Restrictions
Applicant's election with traverse of the following species in the reply filed on June 26, 2024 is acknowledged:
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. Said species is embraced by claims 1-7 and 9-11.
Claims 291-313 are pending and under consideration. Claim 313 is a new claim.
Claim Objections
The objection of claim 311 because of the term solvent being misspelled, is withdrawn based on the amendment.
Claim 291 is objected to because of the following informalities: mandelic salt is redundant on page 3, see lines 5 and 7 in the definition of acids. There may be others. Appropriate correction is required.
Applicant addressed some of the salts, but not all. Thus, objection is maintained.
Claim 306 is objected to because of the following informalities: the term “wherein” is needed after “305,”, see page 6. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The rejection of claim 306 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for the phrase, “wherein the compound of Formula IAA’ contains a bromine,” is withdrawn based on the amendments.
The following is a quotation of 35 U.S.C. 112(b):
(B) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 291-295, 297-304 and 307 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
With regards to claim 307, the compound of formula IAA’ has a different stereochemistry than the compound of formula IAA’ in claim 305 at the H adjacent to the methyl amine which is part of the piperidine ring. Is this correct stereochemistry for the H?
Applicant traverses by stating, “The rejection to claim 307 is traversed. In the description at, for example, page 110 it is stated that "[i]n other examples, Formula IA, IAA, IAA', IAA", or IAA"' is a bromine-containing ergoline derivative such as bromocriptine mesylate." Bromocriptine mesylate is also claimed in the original PCT claim 168 as "168. The method of any one of claims 134 to 167, wherein the compound of Formula IA, IAA, IAA', IAA", or IAA"' is a bromine-containing ergoline derivative such as bromocriptine mesylate." On page 153 bromocriptine mesylate is shown as follows in describing a compound of Formula IAA' (5R,8R), as shown below...
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.”
This is not persuasive. Bromocriptine mesylate does not have same stereochemistry at the R13 bridgehead H and the R14 H as shown in claim 305 from which claim 307 ultimately depends.
Therefore, the rejection is maintained.
In claim 291, the term “ethane, 1,2-disulfonic acid (dihydrate)” is vague. What is being claimed? The dehydrated or the unsolvated compound, or both? Therefore, claims 291-295 and 297-304, since the dependent claims do not remedy the deficiency are rejected.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
Claims 291-313 are rejected under AIA 35 U.S.C. 103(a) as being unpatentable over Kirkland et al. (US 20160237080) in view of Levy et al. (WO 2022232093) and Hardwood et al. ((Experimental Organic Chemistry, Standard and Microscale, 2nd Edition, 1998, pp. 131-143), Perrin et al. (Purification of Laboratory Chemicals, 3rd Edition, 1988, pp. 12-41).
The present application claims a process of making compounds of formula (I), comprising a) hydrolyzing a compound of formula IA to form an intermediate of formula IB, b) reacting the intermediate of formula IB with a compound of formula R1NHR2 to form a compound of formula IC, c) followed by converting a compound of formula IC to a salt or hydrate using an organic or inorganic acid, wherein the final product is the D-tartaric acid salt species shown below.
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The ‘080 reference teaches a process of making compounds of formula (I), which eliminates any registration, importation permits, and/or controlled substances, see paragraph 0005, page 1, comprising a) hydrolyzing a compound of formula IA to form an intermediate of formula IB, b) reacting the intermediate of formula IB with a compound of formula R1NHR2 to form a compound of formula IC, c) followed by converting a compound of formula IC to a salt or hydrate using an inorganic acid, i.e., HCl, see below and present claims 291, 305 and 306.
The ‘080 reference does not have a working example where the D-tartaric acid salt was made. However, on page 3, paragraph 0042, tartaric acid is disclosed. However, making a tartaric acid salt of a compound is considered routine and conventional. The ‘080 reference also teaches tartaric acid from a list of seven acids, see paragraph [0042] 0n page 3.
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The present claims exclude a process of making a compound of formula (I), wherein LSD and/or other schedule I substances are a substrate.
The ‘093 publication teaches using LSD as a substrate, which is the closest prior art compound, to make the D-tartrate salt, see page 19. The ‘093 publication teaches D-tartrate salt as a most preferred embodiment, see page 10, paragraph 000112. The reference further teaches the “salt forms of LSD may exist with varying stoichiometric ratios between the LSD free-base and the acid component of an LSD salt form. One skilled in the art will recognize that this property is not necessarily dependent upon the number of acidic residues present on the acid unit. For example, a mono-acid may form a mono-salt a hemi-salt or an alternate free-base/acid combination. Likewise, a di-acid may form a hemi-salt, a mono-salt, or an alternate free-base/acid combination. It is further understood by one skilled in the art that salt forms with differing stoichiometric ratios between the free-base and the acid components are unique salt forms and may exist in different polymorphic forms,“ see pages 103-104, paragraph [000103]. Moreover, a guidepost for a hemi-salt with tartaric acid and LSD is found in the reference for the D-LSD tartaric acid (+L) hemi-salt, see Figure 2/76, which provides the XRPD spectrum.
Although the present application excludes LSD as a substrate. the ‘093 publication is being used for the motivation to choose and make the D-tartrate salt as any research scientist or a person of ordinary skill in the art would use a reference, where the D-tartrate salt of LSD is made, as a point of reference, unless there is a reason not to or there is evidence to the contrary.
The ‘080 teaches a base catalyzed amide bond with a coupling reagent, step 4, see paragraph 0039 and present claims 292-294.
Claim 295 embraces the precipitation of the products of formula IB and/or IC. Organic chemists may choose to purify intermediates prior to proceeding to the next step of the synthesis to deter any unknown side reactions, remove impurities and/or to characterize the products prior to moving on to the next step. The ‘080 reference teaches that “the disclosure herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present disclosure. It is therefore [to] understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present disclosure as defined by the appended claims,” see paragraph 0046 on page 3.
Moreover, the ‘093 reference provides guidance with solvents, temperatures and times to crystallize or recrystallize salts of a similar compound, LSD, see page 8, paragraph 000105, page 16, paragraph 000154 and 000156; and present claims 296-304 and 308-311. The working example provides a process where a solution of an acid dissolved in ethanol, a homologous solvent of isopropyl alcohol, is combined with a solution of D- LSD free-base in THF, which addresses claim 297. This process does not comprise heating.
Ethanol and isopropyl alcohol (IPA) are homologous solvents. Since a methyl group is considered a homolog of hydrogen these compounds are considered equivalent. The MPEP 2144.09 states “Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).
Even if the ‘093 reference is only used as motivation to choose the D-tartrate salt, making salts of organic compounds is well-known in the art and is a conventional procedure in the lab. More specifically, claims 297-304 and 308-311 can also be addressed with the crystallization or recrystallization references, which will also address the heating portion of claim 297.
Crystallization or recrystallization is a commonly used technique in organic chemistry to purify solid compounds. “The simplest and most effective technique for the purification of solid organic compounds is crystallization. Crystalline compounds are easy to handle, their purity is readily assessed… and they are often easier to identify than liquids or oils. Crystals can be obtained in one of three ways: from the melted
solid on cooling, by sublimation… or from a supersaturated solution. The last method is by far the most common in the organic laboratory,” see the Crystallization paragraph on page 131 of the Hardwood reference.
Hardwood goes on to state, “The process involves five stages: dissolution.
filtration. crystallization. collection of the crystals. and drying the crystal,” see the last two lines on page 131. On page 132, the reference states, “The technique involves dissolving the impure solid in the minimum volume of a hot solvent and filtering to remove insoluble impurities. The resulting hot saturated solution of the compound, together with any soluble impurities, is set aside to cool slowly, whereupon crystals of pure compound will separate from solution,” see the bottom paragraph on page 132.
The Perrin reference teaches solvents commonly used for crystallizations, see page 14, last line, and page 40, Table 5, which teaches ethanol. The Perrin reference goes on to state, “Where a substance is too soluble in one solvent and too insoluble in another, for either to be used for recrystallisation, it is often possible (provided they are miscible) to use them as a mixed solvent. (In general, however, it is preferable to use a single solvent if this is practicable.) Table 6 comprises many of the common pairs of miscible solvents,” see page 15, first paragraph. Thus, purification of the same general approach used for single-solvent dissolution is followed when mixed solvents (solvents and anti-solvents) are employed.
The solution is allowed to cool to allow for crystal formation (crystallization will be better if this step takes place slowly). After the system reaches room temperature, cooling it in an ice bath may improve the yield. Then the solid product is isolated by filtration. The crystals normally are washed with a small amount of cold solvent during the filtration step.
The choice of solvent is perhaps the most critical step in the process of crystallization since the correct solvent must be selected to form a product of high purity and in good recovery or yield. This is considered routine optimization unless there is evidence to the contrary. 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. "Where 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, 105 USPQ 233, 235 (CCPA 1955). Accordingly, this type of modification would have been well within the purview of the skilled artisan and no more than an effort to optimize results.
With regards to claims 300 and 312, the ‘080 reference teaches the end product may be crystalline and may have a number of polymorphic forms, see page 3, paragraph 0044. The ‘093 reference also teaches a crystalline product and polymorphic forms, see page 8, paragraph 000106.
Claims 304, 311 and 312 are drawn to purity. However, purity can be increased at the cost of a lower yield by recrystallizing the final product over and over again to obtain a product higher in purity.
Claim 307 is drawn to a starting compound with the following structure:
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. The use of analogous reactants in a known process is prima facie obvious. In re Durden, 226 USPQ 359 (1985). Once the general reaction has been shown to be old, the burden is on Applicants to present reasons or authority for believing that a group on the starting material would take part in or affect the basic reaction and thus alter the nature of the product or the operability of the process. In looking at the instant claimed process as a whole, as stated in In re Ochiai, 37 USPQ 2d 1127 (1995), the claimed process would have been suggested to one skilled in the art.
Thus, said claims are rendered obvious by Kirkland et al. in view of Levy et al, and the Recrystallization reference.
Applicant traverses by stating, “In the present case, there is no enabling methodology in Kirkland nor Levy for practicing the claimed invention., nor is there any suggestion to modify the methodology of Kirkland with the teachings of Levy, nor any evidence suggesting that those modifications would be successful.”
This is not persuasive. The Kirkland (‘080) reference provides the motivation to make an LSD analogue, which eliminates any registration, importation permits, and/or controlled substances, see paragraph 0005, page 1. The Levy (‘093) reference provides motivation to make the hemi-D-tartaric acid salt as a most preferred embodiment.
Applicant further traverses by stating, “Kirkland does not teach a method of making a Lysergic Acid Diethylamide (LSD) compound of Formula I, as recited in amended claim 291. Kirkland discloses a general scheme of making the claimed compound; however, there are no experimental examples. The methodology relied on by the Examiner is very broadly stated and is prophetic in nature. There is no detailed teaching within Kirkland to enable a person of ordinary skill in the art to successfully make the compound.”
Again, this is unpersuasive.
Kirkland does not have experimental examples of synthesizing a lysergic acid diethylamide (LSD) compound of Formula I, as recited in amended claim 291. However, Kirkland properly describes a method of making a compound similar to lysergic acid diethylamide (LSD) compound of Formula I, as recited in amended claim 291, as noted in the rejection, see paragraphs [0020]-[0043]. Although Kirkland does not teach a method of actually recovering a crystalline product, said method is conventional in a chemical lab to purify products as noted by Hardwood and Perrin.
Applicant further traverses by noting, “Kirkland has NO working examples that read on the amended claims, contrary to the Examiner's statements. Paragraph [0042] of Kirkland merely lists examples of possible acidic salts, where acidification is stated to be in a wide range of conditions - since it was not done. Paragraphs [0043]-[0044] confirm that Kirkland makes a guess of what may be formed.”
This also is not persuasive. Indeed, Kirkland has no working example that read on the amended claims. However, the combination of references renders obvious the amended claims, as noted in the rejection.
Applicant further notes, “The rejection relies on Levy to teach the D-tartaric acid recited in the claims. Levy teaches a laundry list of acids. However, there is no motivation within Levy to chose D- tartaric acid from the laundry list of acids taught within the reference. D tartrate is not taught as a most preferred salt, in fact, there is the one example at paragraph 187.2 Further, it should be noted that this is the stoichiometric salt, 1 LSD to 1 tartrate, while the claimed method makes the hemi-salt, 1 LSD to 0.5 tartrate. Levy does generally disclose a hemi L-tartrate, but could not form one with D-tartrate. While the advantage of the hemi-salt may not be apparent to the Examiner, it should be noted that the hemi-salt is electrically balanced while the salt has an excess of negative charge that must be balanced by another cation in the crystal lattice, hydrogen or sodium, for example. These salts are therefore subject to contamination by another cation. Finally, although Levy discloses both a D-tartrate and an L-tartrate salt, it is surprising and unexpected that enantiomer counter-ions form crystals with the 2-bromo-LSD. Finally, although LSD is similar to 2-bromo-LSD in many ways, replacing a hydrogen with a bromine produces a more electronegative center, which would produce a repulsive force on a counter-ion like tartrate, so for the purpose of forming a crystalline salt, examples of the LSD salts of Levy really do not predict or describe 2-bromo- LSD salts as made by the claimed method.”
This is unpersuasive. The reference states in paragraph [000112], “In a most preferred embodiment, the salt form of LSD comprises LSD and an acid selected from maleic acid, L-tartaric acid, D-tartaric acid, phosphoric acid, xinafoic acid, oxalic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, L-ascorbic acid, fumaric acid and benzoic acid.” The Examiner was quoting the reference for a most preferred embodiment.
The reference further teaches the “salt forms of LSD may exist with varying stoichiometric ratios between the LSD free-base and the acid component of an LSD salt form. One skilled in the art will recognize that this property is not necessarily dependent upon the number of acidic residues present on the acid unit. For example, a mono-acid may form a mono-salt a hemi-salt or an alternate free-base/acid combination. Likewise, a di-acid may form a hemi-salt, a mono-salt, or an alternate free-base/acid combination. It is further understood by one skilled in the art that salt forms with differing stoichiometric ratios between the free-base and the acid components are unique salt forms and may exist in different polymorphic forms,“ see pages 103-104, paragraph [000103]. Moreover, a guidepost for a hemi-salt with tartaric acid and LSD is found in the reference for the D-LSD tartaric acid (+L) hemi-salt, see Figure 2/76, which provides the XRPD spectrum.
Applicant further notes, “Hardwood and Perrin merely teach the general practice of making salts and crystals. Nowhere do they teach the claimed method, the aim of the claimed method, nor do they predict making the claimed compound of Formula I or crystal polymorphs thereof. Accordingly, the combination of Kirkland, Levy, Hardwood, and Perrin, alone or in combination, do not teach or suggest the claimed method.”
Indeed, the Hardwood and Perrin references teach the general practice of making salts and crystals to support these techniques are well-known routine and conventional in an organic chemistry lab.
Thus, the rejection is maintained.
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 claims at issue 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); and 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 291-313 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 12331051. Although the conflicting claims are not identical, they are not patentably distinct from each other because the present claims are drawn to making a D-tartaric acid salt of a compound of formula (I).
The claims in the ‘051 patent are drawn to the compounds.
There is no patentable distinction between the compounds and methods of making the compounds.
Conclusion
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/SUSANNA MOORE/Primary Examiner, Art Unit 1624
