Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of the invention of Group II (claims 15-19, directed to methods of treating) in the reply filed on 04/03/2025 is acknowledged. Applicants additional elections of the particular species that are: the combination of genetic biomarkers and enzymatic-related elements (i.e.: parts (i) and (iii) in claim 18); the particular AKR1C1 variant that is p.Leu54Val; and the particular metabolite that is 20α-Hydroxy-pregn-4-ene-3-one; the particular activity of AKR1C1 (relevant to claim 15); and the particular compound that is glycyrrhetinic acid; are also acknowledged.
Claims 1-14 and 20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and claim 17 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a species (i.e.: requiring non-elected prostaglandin-modulating compounds), there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/02/2025.
Claim Rejections - 35 USC § 112 - Indefiniteness
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 15, 16, 18 and 19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 15, 16, 18 and 19 are unclear over recitation of the phrase “preferably contained in a food supplement, cream or ointment”, as recited in claim 15 from which claims 16, 18 and 19 depend. It is unclear if the elements recited as “preferably” are intended to be required elements of the claims, or if they are required to in some specific way modify the therapeutic compound that is required in the claimed methods.
Claim 16 is unclear over recitation of the phrases “in particular”, “such as”, “preferably”. Similar to the issue raised above, the it is unclear if the elements recited as “in particular”, “such as”, “preferably” are intended to be required elements of the claim, or if they are required to in some specific way modify the therapeutic compounds that are recited in the claimed methods.
Claim 16 is rejected over recitation of the limitations “indicated in table 6” and “indicated in table 8”. MPEP 2173.05 (s) provides guidance on the recitation of tables from the specification as claim limitations:
Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993).
In the instant case the claim may be amended to rection a particular element consonant with the elections.
Claims 18 and 19 unclear over recitation of the limitations “(iv) identifying natural and synthetic molecules capable of modulating AKR1C1 with possible therapeutic effect on lipedema”, because this step does not appear to be suitable for “diagnosis of lipedema”, as required by the limitations of claim 18.
Claim Rejections - 35 USC § 112 - Improper Markush Group
Claims 15, 16 18 and 19 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
In claim 15, the Markush grouping of different therapeutic targets of: activity of AKR1C1; and activity of prostaglandins, is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: The different therapeutic targets are structurally unique (AKR1C1 is a protein enzyme composed of amino acids; prostaglandins are lipids with hormone-like properties) which may be modulated by compounds which are themselves structurally distinct, as evidenced by the different compounds disclosed in the instant specification as related to AKR1C1 modulation (e.g.: Tables 6 and 8) versus the distinct compounds related to prostaglandin modulation (Table 7).
In claim 16, the Markush grouping of different compounds is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: While the compounds are asserted to have a common function in the treatment of lipedema related to modulation of AKR1C1, these compounds are structurally distinct from each other and may in fact impart there modulating activity via different mechanisms. Consider the elected glycyrrhetinic acid, which is a pentacyclic triterpenoid derivative of the beta-amyrin type obtained from the hydrolysis of glycyrrhizic acid, as compared to benzodiazepines whose core chemical structure is the fusion of a benzene ring and a diazepine ring.
In claim 18 the Markush grouping of different diagnostic elements recited as parts (i), (ii), (iii) and (iv) is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: These different processes require the detection of structurally distinct elements (e.g.: gene sequences; small molecule metabolites) that may require different reagents and equipment (e.g.: nucleic acid probes; antibodies) that are themselves structurally unique and require distinct techniques and methodological procedures.
The rejection of claims for recitation of an improper Markush grouping may be addressed by amendment of the claims to recite particular elements consonant with Applicants’’ elections.
Claim Rejections - 35 USC § 112 – Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 15, 18 and 19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant rejection of claims for lack of an adequate written description of the claimed subject matter is relevant to several aspects of the claims.
As a first aspect, the claims are broadly directed to the treatment or prevention of lipedema in a subject comprising administration of a compound suitable for modulating the activity of AKR1C1 (as consonant with the election). The breadth of the structures of the compounds is generic and encompasses any sort of nucleic acid-based therapeutic, small molecule, antibody, or biological therapeutic compound. Furthermore, while the target of the compound is identified in the claim as AKR1C1 (as consonant with the election), the effect of the compound is generically recited as “modulating the activity of AKR1C1”. Thus, the compound may have any effect on AKR1C1 activity: increasing activity, decreasing activity, altering substrate specificity, changing the product of the enzyme. And while the specification provides several different compounds asserted to have an effect of activation or inhibition of AKR1C1, the disclosure of these particular compounds does not provide any common structural elements of the different compounds such that the skilled artisan can discern, a priori, that any other compound would have a similar functionality. And while the claims generically encompass any modulation of AKR1C1, the claims also require that administration of the compound is for the treatment and/or prevention of lipedema. In this regard it is noted that the specification appears to be equivocal as to what sort of modulation (e.g.: increase or decrease) of AKR1C1 activity would be suitable for the therapeutic effect. The specification asserts (e.g.: para [0009]) that “the enzyme expressed by this gene, the 20α-hydroxysteroid dehydrogenase (20α-HSD), metabolizes progesterone and causes over production of subcutaneous adipocytes”. This reasoning would appear to provide that an inhibitor of AKR1C1 would treat lipedema (because the activity of the enzyme causes over production of subcutaneous adipocytes). But the specification also teaches (e.g.: para [0012]-[0013]) that loss-of-function mutations in the AKR1C1 gene have been found in lipedema patients, and that “partial loss-of-function resulting in a slower and less efficient reduction of progesterone to hydroxyprogesterone and an increased subcutaneous fat deposition in variant carriers”. This reasoning would appear to provide that an activator of AKR1C1 would treat lipedema (because a more active enzyme would provide faster and more efficient reduction of progesterone to hydroxyprogesterone and a decrease subcutaneous fat deposition).
Thus, the specification as filed does not provide any blaze marks for the skilled artisan to identify other compounds that may have a general function related to the modulation of AKR1C1 activity; nor does the specification provide the skilled artisan with the ability to identify any particular type of activity modulation that would be suitable for lipedema treatment and/or prevention.
As a second aspect, the claims are directed to methods that include the diagnosis of lipedema in a subject, and broadly encompass the detection of any “are and polymorphic variants in the sequence of AKR1C1 gene, copy number variants (CNV), complex rearrangements and epigenetic modifications”. The structures of the genetic elements encompassed by the claims are broad, including but not limited to any amino acid substitutions, insertions or deletions, frameshifts, translocation and rearrangements anywhere in the AKR1C1 gene (e.g.: introns, exons, promoters, upstream or downstream regulatory elements). However, while the specification provides (e.g.: para [0012]; Tables 1 and 2) only several specific AKR1C1 variants, and teaches the detection of only a few mutations (e.g.: p.Leu54Val; p.Leu53Phe; p.Leu213Gln) as being identified in lipedema patients. This is particularly relevant where there are thousands of variants (see for example the GeneCards output for the human AKR1C1 gene) in the AKR1C1 gene. The specification does not provide the skilled artisan with a basis for determining which of the myriad of encompassed variants/mutations/alterations would be indicative of a lipedema. The specification does not provide the skilled artisan with the ability to a priori select from the broadly encompassed structural genus of any variant AKR1C1 gene those particular biological sequences that satisfy the functional limitations of the subgenus of variants that are indicative of a lipedema.
As a second aspect, the claims are directed to methods that include the diagnosis of lipedema in a subject, and broadly encompass the detection of any “increment or reduction of AKR1C1 enzymatic substrate or product or metabolites, in a biological sample of a lipedema patient compared to controls”. As such the claims encompass detection of a wide variety of analytes (e.g.: any substrates or products of AKR1C1, or any downstream metabolites of the products), and includes any levels of those analytes (e.g.: increased or decreased as compared to any control). The lack of any particular control is relevant considering possible variations in gene expression in even similar samples. Cheung et al (2003) teaches that there is natural variation in gene expression among different individuals. The reference teaches an assessment of natural variation of gene expression in lymphoblastoid cells in humans, and analyzes the variation of expression data among individuals and within individuals (replicates) (p.422, last paragraph; Fig 1). The data indicates that, for example, expression of ACTG2 in 35 individuals varied by a factor of 17; and that in expression of the 40 genes with the highest variance ratios, the highest and lowest values differed by a factor of 2.4 or greater (Fig 3). And here it is noted that the claims encompass any alteration (increase or decrease) of any of the analytes in the diagnosis of lipedema. But, as noted above, the specification is equivocal concerning whether it is a gain of function, or a loss of function, of AKR1C1 which is indicative of lipedema.
Given the breadth of the claims, the functional requirements of the claims, and the teachings of the specification, it is the conclusion that the application as filed fails to provide an adequate written description of the claimed subject matter.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
In the rejection of claims under 35 USC 102 it is noted that the claims were previously rejected under 35 USC 112(a) as lacking adequate written description in the application as filed. In the instant case, while the cited prior art anticipates a specific embodiment encompassed by the breadth of the rejected claims, the prior art does not itself provide a teaching adequate to supply a description of the generic breadth of the claimed subject matter.
Claim(s) 15 and 16 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Weber et al (US PG Pub 20180207078 A1).
Relevant to the rejected claims, Weber et al teaches treatment of human subjects for lipedema (recited in the prior art with the alternate spelling of “lipoedema”) using glycyrrhetinic acid (e.g.: para- 0002, 0005, 0012, 0014, 0153; claims 33 and 36 on page 17).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
In the rejection of claims under 35 USC 103 it is noted that the claims were previously rejected under 35 USC 112(a) as lacking adequate written description in the application as filed. In the instant case, while the cited prior art renders obvious a specific embodiment encompassed by the breadth of the rejected claims, the prior art does not itself provide a teaching adequate to supply a description of the generic breadth of the claimed subject matter.
Claim(s) 15, 16, 18 and 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Weber et al (US PG Pub 20180207078 A1) in view of Michelini et al (2020) as cited on the IDS of 05/10/2022.
With regard to claims 15 and 16, Weber et al teaches treatment of human subjects for lipedema (recited in the prior art with the alternate spelling of “lipoedema”) using glycyrrhetinic acid (e.g.: para- 0002, 0005, 0012, 0014, 0153; claims 33 and 36 on page 17).
Weber et al does not teach confirmation of a diagnosis of lipedema comprising the detection of (as constant with the election) variants in the AKR1C1 gene (relevant to step (i) of claim 18) and the detection of a compared level of an AKR1C1 enzymatic substrate, product or metabolite) (relevant to step (iii) of claim 18).
However, the association of a mutation in AKR1C1 with the lipedema pathology, as well as the effect of the mutation on AKR1C1 enzymatic products, was known in the prior art and is taught by Michelini et al.
Relevant to the rejected claims, Michelini et al teaches a pedigree analysis and whole exome sequencing in a lipedema family, and teaches that with the L213Q variant is present in affected subjects (e.g.: Figure 1). Michelini et al further teaches that the effect of the genetic variant of AKR1C1 was investigated in silico with bioinformatic tools and suggests a partial loss-of-function (LoF) associated with the variant; and that AKR1C1 predominantly inactivates progesterone into 20-α-hydroxyprogesterone via its 20α-HSD activity, indirectly regulating the adiposity of subcutaneous fat.
It would have been prima facie obvious to someone with ordinary skill in the relevant art before the effective filing date of the rejected claims to have included steps of diagnosing lipedema, as suggested by Michelini et al, with the treatment of lipedema using glycyrrhetinic acid that is taught by Weber et al. The skilled artisan would have been motivated to use diagnostic elements related to lipedema to provide a diagnosis based on the expressed teachings of Michelini et al that the pathology is underdiagnosed; the skilled artisan would recognize that the elements taught by Michelini et as associated with lipedema would aid in the diagnosis of the pathology that is treated by the methods of Weber. Where Michelini et al teaches that a particular mutation is associated with the presence of lipedema, the skilled artisan would recognize that detecting the mutation in a subject would be indicative of an increased likelihood of lipedema in the subject. Furthermore, where Michelini et al teaches that the particular mutation provides a partial LoF of the AKR1C1 enzyme which predominantly inactivates progesterone into 20-α-hydroxyprogesterone, the skilled artisan would recognize that a decreased amount of the enzymatic product 20-α-hydroxyprogesterone in a subject, as compared to a healthy control, would be indicative of the presence of a gene alteration associated with lipedema. Thus, the detection of the particular variant of Michelini et al, and levels of an enzymatic product that is a consequence of the presence of the particular variant, would aid in the diagnosis of lipedema and the subsequent treatment of the pathology.
Requirement for Information
Applicant and the assignee of this application are required under 37 CFR 1.105 to provide the following information that the examiner has determined is reasonably necessary to the examination of this application.
The Examiner has identified the following citation/reference that is relevant to the instantly claimed subject matter:
Maltese, P. E., Manara, E.; Paolacci, S.; Marceddu, G.; Michelini, S.; Bertelli, M. “Target and whole exome sequencing in families with lymphedema and lipedema” (Meeting Poster) European Biotechnology congress. Valencia, Spain. April 11 -13, 2019.
Cited in: Journal of Biotechnology, (Nov. 15, 2019) vol. 305, No. suppl. S, pp. S7.
The authorship of the cited Abstract includes inventors of the instant application.
The Examiner requires additional information in order to make further determinations about the patentability to the instant claims. In response to this requirement, please provide answers and relevant information to each of the following:
1. Applicant is required to provide a copy of any material presented in association with the abstract (e.g.: poster presentation materials).
2. Was the gene of instantly claimed methods (i.e.: AKR1C1) include in any part of any presented materials?
The fee and certification requirements of 37 CFR 1.97 are waived for those documents submitted in reply to this requirement. This waiver extends only to those documents within the scope of this requirement under 37 CFR 1.105 that are included in the applicant’s first complete communication responding to this requirement. Any supplemental replies subsequent to the first communication responding to this requirement and any information disclosures beyond the scope of this requirement under 37 CFR 1.105 are subject to the fee and certification requirements of 37 CFR 1.97.
The applicant is reminded that the reply to this requirement must be made with candor and good faith under 37 CFR 1.58, Where the applicant does not have or cannot readily obtain an item of required information, a statement that the item is unknown or cannot be readily obtained may be accepted as a complete reply to the requirement for that item.
This requirement is an attachment of the enclosed Office action. A complete reply to the enclosed Office action must include a complete reply to this requirement. The time period for reply to this requirement coincides with the time period for reply to the enclosed Office action.
Conclusion
No claim is allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Paolacci et al (2019) provide a prior art review of genetic components related to lipedema, but the reference does not teach that AKR1C1 was a known or suspected gene associated with lipedema.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHEN THOMAS KAPUSHOC whose telephone number is (571)272-3312. The examiner can normally be reached M-F, 8am-5pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Cynthia Wilder can be reached on (571) 272-0791. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
Stephen Kapushoc
Primary Examiner
Art Unit 1684
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683