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 .
Priority
Acknowledgments are made that this application claims the priority to the following:
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Information Disclosure Statement
The information disclosure statement (IDS), dated 12/14/2023, comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, they have been placed in the application file and the information therein has been considered as to the merits.
Response to Restriction
Applicant's response to restriction requirement and election of group I corresponding to claims 1-9, without traverse, in the reply filed on 05/18/2026 is acknowledged.
Claims 10-16 are withdrawn from consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
The examiner also acknowledges applicants response to election of species and providing a single species for the claimed glucagon analog. Following an extensive search and examination, the originally elected species has been deemed free of the prior art. Per MPEP § 803.02, “If the examiner determines that the elected species is allowable over the prior art, the examination of the Markush claim will be extended”. Accordingly, the search has been extended to the full scope of claimed method. The broadest genus has been rejected under 35 USC 112(a) and 103 as explained below.
The claims 1-9 are examined on merits in this office action.
Claim Objections/Sequence Compliance
Claim 1 is objected to because of the following informalities: 37 CFR 1.821(d) states that where the claims recite a sequence, having at least 4 amino acids, then the sequence identifier must be included. The applicants have provided a sequence listing, but have not included the corresponding sequence identifiers in claim 1.
Appropriate correction is required.
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 1-9 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 for the claimed method. 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The rejection is based on the requirement(s), i.e., the guidelines provided by the MPEP 2163.04. These are listed below:
(A) identify the claim(s) limitations at issue, and
(B) establish a prima facie case by providing reasons why a person skilled in the art at the time the application was filed would not have recognized that the inventor was in possession of the invention as claimed in view of the disclosure of the application as filed. The MPEP 2163 further provided or expanded the guidelines for the written description requirements.
(A) IDENTIFY THE CLAIM LIMITATIONS AT ISSUE:
Independent claim is drawn to a glucagon analog or its salt/solvate form having a structure of formula (I), wherein the variables, viz., X3, X15, X20, X21, X24, X27, and X28 are independently selected from the group consisting of any natural and unnatural amino acid residues, and X17 is Aib.
In the above, the claimed variables can be any natural and unnatural amino acid residues. For example, all variables can be Cys or positively charged amino acids or negatively charge amino acids or combination thereof.
Dependent claims further limit the variables with the recited specific amino acids. These can be hydrophobic or positively charged or negatively charged or polar amino acids. For example, X20/X24 can be hydrophobic, negatively charged or positively charged amino acid.
Specification defined the term “glucagon analog” refers to a compound having at least a part of, all of, or more agonist activity of the native glucagon for a glucagon receptor. For example, the glucagon analog includes, but is not limited to: a polypeptide comprising any amino acid substitution, insertion or deletion, or a post-translational modification or other chemical modification on the basis of an amino acid sequence set forth in SEQ ID NO: 51, provided that the analog has activity in stimulating the glucagon receptor, e.g., as determined by cAMP production according to the method described in Example 2.
Based on its definition of glucagon analog and claimed variables, claimed formula (I) can generate hundreds or more peptides, encompasses several of patentably distinct species. The physical and chemical properties expected to be drastically different for the resulted peptides.
The claimed glucagon analog is associated with a property similar to natural glucagon. Structure or conformation of peptide or protein is very sensitive to environmental changes. Small change in the primary sequence, such as substitution of amino acids, may drastically alter overall property of the glucagon analog.
To support the above broadly claimed subject matter, specification exemplified or described the properties of glucagon analogs with SEQ ID NOs: 39-43 and 47, specifically limited to SEQ ID NO:40. It appears that substitutions are limited to exchange of negatively charged amino acid with other negatively charged amino acid, hydrophobic with other hydrophobic amino acids etc. No data or description is provided with all possible natural or unnatural amino acids, as broadly claimed glucagon. Specification also failed to describe the nexus between the shown data and broadly claimed subject matter. In other words, the structure/function relationship for the claimed generic variables and claimed glucagon analog is not described.
Applicants can claim as broadly as possible for the claimed invention. However, if there is a divergency in the genus or broadly claimed subject matter, and if it expects unpredictability for the claimed subject matter, then specification must describe the genus with divergent species, so that a skilled person in the art can understands claimed invention and can reproduce applicants claimed method. In this case, at least protein chemistry is probably one of the most unpredictable areas of biotechnology and consequently, the effects of sequence dissimilarities upon protein structure and function cannot be predicted. So, in absence of description for divergent species makes the invention unpredictable, and cannot be envisioned by a skilled person in the art.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include "level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient" (MPEP 2163).
A claimed genus may be satisfied through sufficient description of a representative number of species or disclosure of relevant, identifying characteristics such as functional characteristics coupled with a known or disclosed correlation between function and structure. See MPEP 2163 II(A)(3)(a)(ii).
The number of species that describe the genus must be adequate to describe the entire genus. However, if there is substantial variability, a large number of species must be described.
The question is with several hundreds of possible divergent species in all possible combinations, (i) did applicants provide enough description for making all possible peptides and (ii) will the these be capable of retain its property? Based (i) and/or (ii), will a skilled person in the art understand and can reproduce applicants claimed invention?
(B) ESTABLISH A PRIMA FACIE CASE BY PROVIDING REASONS WHY A PERSON SKILLED IN THE ART AT THE TIME THE APPLICATION WAS FILED WOULD NOT HAVE RECOGNIZED THAT THE INVENTOR WAS IN POSSESSION OF THE INVENTION AS CLAIMED IN VIEW OF THE DISCLOSURE OF THE APPLICATION AS FILED:
The further analysis for adequate written description considers, see MPEP 2163, the following:
(A) Determine whether the application describes an actual reduction to practice of the claimed invention:
Not provided. The claimed genus of glucagon analogs can generate hundreds of divergent species. Specification merely describes a theoretical approach for the claimed subject matter.
Example 1 describes various glucagon analogs (SEQ ID NOs:1-49) and their synthesis.
Example 2 describes agonist activities of SEQ ID NOs: 39-43 and 47.
Example 3 describes solubilities of SEQ ID NOs: 2-5, 38-43 and 47. Seems there is not much difference in the solubility data compared to Dasiglucagon.
Example 4 describes physical and chemical stability of SEQ ID NOs: 39-41. Seems there is not much difference in the solubility data compared to Dasiglucagon.
Examples 5-9 describes biological properties of glucagon analog, but the data is limited to SEQ ID NO:40.
In the above, only Examples 2 and 5-9 show the biological properties of glucagon analogs. It appears that glucagon properties are limited to SEQ ID NO:40. Also, substitutions are limited to exchange of negatively charged amino acid with other negatively charged amino acid, hydrophobic with other hydrophobic amino acids etc. No data or description is provided with all possible natural or unnatural amino acids, as broadly claimed glucagon. Specification also failed to describe the nexus between the shown data and broadly claimed subject matter.
So, the provided data is very limited.
Accordingly, applicants failed to describe actual reduction to practice of the claimed invention.
(B) If the application does not describe an actual reduction to practice, determine whether the invention is complete as evidenced by a reduction to drawings or structural chemical formulas that are sufficiently detailed to show that applicant was in possession of the claimed invention as a whole:
Figures are also limited to SEQ ID NOs: 38-41.
So, as evidenced from the above description of drawings, it is clear that the claimed invention is not complete by a reduction to drawings or structural chemical formulas that are sufficiently detailed to show that applicant was in possession of the claimed invention as a whole.
(C) If the application does not describe an actual reduction to practice or reduction to drawings or structural chemical formula as discussed above, determine whether the invention has been set forth in terms of distinguishing identifying characteristics, such as structure/function correlations, as evidenced by other descriptions of the invention that are sufficiently detailed to show that applicant was in possession of the claimed invention:
Although glucagon is known to be effective for treating type 2 diabetics and over weight etc., this does not translate sufficiently for the genus of possible analogs of claim 1 that comprises 9 modifications at specified positions with the specified divergent amino acids to conclude possession even of a subset of the genus of claim 1 for such property.
At least, in the broadly claimed peptides, which can have all possible combination of amino acids in their sequences at 8 positions in claims 1 and recited divergent amino acids in dependent claims, a skilled person in the art cannot envision applicants claimed subject matter, since protein chemistry is probably one of the most unpredictable areas of biotechnology. Consequently, the effects of sequence dissimilarities upon protein structure and function cannot be predicted.
For example, Bowie et al (Science, 1990, 247:1306-1310) teach that an amino acid sequence encodes a message that determines the shape and function of a protein and that it is the ability of these proteins to fold into unique three-dimensional structures that allows them to function and carry out the instructions of the genome and further teaches that the problem of predicting protein structure from sequence data and in turn utilizing predicted structural determinations to ascertain functional aspects of the protein is extremely complex (column 1, page 1306). Bowie et al further teach that while it is known that many amino acid substitutions are possible in any given protein, the position within the protein's sequence where such amino acid substitutions can be made with a reasonable expectation of maintaining function are limited. Certain positions in the sequence are critical to the three dimensional structure/function relationship and these regions can tolerate only conservative substitutions or no substitutions at all (column 2, page 1306). The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al (Mol. Cell. Biol., 8:1247-1252, 1988) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
In view of above evidences, applicants have claimed wide range of peptides and all possible combinations, and a skilled person in the art can expect unpredictability in the broadly claimed genus. There are no physical/chemical/structural features that applicants have tied to this property in a relevant teaching manner, making it impossible for an individual of ordinary skill in the art to determine which of the very large genus of claimed peptides would be effective. Without a correlation between structure and function, the claims do little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement.
Applicants have failed to provide guidance or data or evidence as to how the skilled artisan would be able to extrapolate from the disclosure species to make and possibly use of the claimed invention. “A description of what a material does, rather than of what it is, usually does not suffice." Rochester, 358 F 3d at 923; Eli Lilly, 119 at 1568. Instead, the “disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described.”
Vas-Cath Inc. Mahurkar, 19 USPQ2d 1111, makes clear the "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116).
Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of the claimed subject matter and does not reasonably convey to one skilled in the relevant art that the inventors had possession of the entire scope of the claimed invention.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis 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 of this title, 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 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 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.
Claims 1-2 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Riber (US2015/0210744A1).
Riber teaches the following sequence:
HSQGT FTSDY SKYLD SARAE DFVAW LEST [see SEQ ID NO:5], wherein bold and underlined amino acids are corresponds to applicants X3, X15, X16, X17, X20, X21, X24, X27, and X28.
The above sequence falls within the scope of applicants’ glucagon analog of formula I, when in the applicants formula I, R1 is hydrogen, X3 is Gln (Q), X15 is Asp (D), X16 is Ser, X17 is Ala (A), X20 is Glu (E), X21 is Asp (D), X24 is Ala (A), X27 is Glu (E), X28 is Ser (S), R1 is H and R2 -OH, since there are no substitutions on N- and C-terminus amino acids.
Difference is that Riber teaches Ala at X17, whereas claims require Aib (2-AminoIsoButyric acid or α-methylalanine).
The above difference is interpreted as replacement of H with methyl group on alanine. However, the issue of patentability over the replacement of alkyl groups for hydrogen or vice versa has arisen many times. For instance, the replacement of a methylene group with a dialkyl-substituted methylene group was determined to be prima facie obvious on the ground that "one skilled in the art would have been, prima facie, motivated to make the claimed compounds in the expectation that they, too, would possess antimicrobial activity." (In re Wood 199 USPQ 137) See also In re Doebel 174 USPQ 158 (where replacement of methyl for hydrogen on an amino nitrogen was considered prima facie obvious - at page 159); In re Druey 138 USPQ 39 (where replacement of methyl for hydrogen on a known compound was considered prima face obvious based on the homologous and close structural relationship to the known compound - at page 41); In re Lohr 137 USPQ 548 (where the replacement of a methyl group for a hydrogen on two positions of a tetrahydropyran ring on a known compound was not considered a patentable modification given the close structural relationship to the known compounds - at page 550); Ex parte Bluestone 135 USPQ 199 (where fungicidal compounds differing by hydrogen versus methyl on the nitrogen of a thiazolidine-2-thione ring were considered homologs and were not found to be patentable over each other without a showing of unexpected results - at page 200); Ex parte Weston 121 USPQ 429 (where the replacement of methyl for hydrogen on the nitrogen of a piperazine ring was not found to be a patentable modification).
The motivation to make a substitution of an alkyl group for hydrogen stems from the fact that a person having ordinary skill in the art would expect that the compounds could be prepared by the same method as taught by the prior art and have the same utility as the compounds taught by the prior art.
MPEP 2144.09 (VII) states “A prima facie case of obviousness based on structural similarity is rebuttable by proof that the claimed compounds possess unexpectedly advantageous or superior properties. In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963)”.
Based on the above established facts from the cited prior art, it appears that all the claimed elements, i.e, applicants modifications in the peptide, were known in the prior art, and one skilled person in the art could have modified the elements as claimed by known relationships, with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art.
The motivation to modify the art can arise from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combined for their common known purpose. See MPEP 2144.07. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention by taking the advantage of the teaching of the above cited reference and to make the instantly claimed method with a reasonable expectation of success.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SUDHAKAR KATAKAM whose telephone number is (571)272-9929. The examiner can normally be reached 8:30 am to 5 pm.
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SUDHAKAR KATAKAM
Primary Examiner
Art Unit 1658
/SUDHAKAR KATAKAM/Primary Examiner, Art Unit 1658
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