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 .
Clarification
For reasons internal to the USPTO, this application has been reassigned. The present examiner regrets if this is inconvenience to applicant(s).
Priority
Acknowledgments are made that this application claims the priority to the following:
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Information Disclosure Statement
Filed information disclosure statement (IDS) is 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 1-23, with traverse, in the reply filed on 01/12/2026 is acknowledged.
The examiner also acknowledges applicants response to election of species and providing a single species for the claimed variables. It appears that applicants elected species are free of art. 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 group. The broadest genus has been rejected under 35 USC 112(a) as explained below.
Non-elected group claims 24-25 are withdrawn from consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.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 claims 1-23 are examined on merits in this office action.
Sequence Non-compliance
The claims 1 and 21 are objected because of the following informalities: Claims define at least 4 amino acids are specifically defined in the definition of group X and recited compounds in claim 21. So, claims fail to comply with 37 CFR 1.821 (a)-(d) which requires reference made to transmembrane sequence(s) by use of the sequence identifier, preceded by "SEQ ID NO:" in the text of the claim, even if the sequence is also embedded in the text of the claims of the patent application. See MPEP §2422. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claim 20 is 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.
Claim is vague. The second paragraph of 35 U.S.C. 112 requires that the claim particularly point out the invention. Claims may not refer to the Specification. Verily, claims that refer to the specification are improper. See Ex parte Fressola, 27 USPQ.2d 1608 (BPAI 1993). Claim improperly refers to compounds to Examples 1-33.
The above-mentioned rejection under 35 U.S.C. § 112, 2nd will be obviated by the following suggestions: inserting the compounds into the claim.
Claim Rejections - 35 USC § 112(a) [Scope of Enablement]
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 1-23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a compound of formula (I) or salt or zwitterion thereof, does not reasonably provide enablement for prodrug thereof. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
“The [eight] factors to be considered [in making an enablement rejection] have been summarized as a) the quantity of experimentation necessary, b) the amount of direction or guidance presented, c) the presence or absence of working examples, d) the nature of the invention, e) the state of the prior art, f) the relative skill of those in that art, g) the predictability or unpredictability of the art, h) and the breadth of the claims”, In re Rainer, 146 USPQ 218 (1965); In re Colianni, 195 USPQ 150, Ex parte Formal, 230 USPQ 546.
a) Finding a prodrug is an empirical exercise. Predicting if a certain ester of a claimed alcohol, for example, is in fact a prodrug, that produces the active compound metabolically, in man, at a therapeutic concentration and at a useful rate is filled with experimental uncertainty. Although attempts have been made to predict drug metabolism de novo, this is still an experimental science. For a compound to be a prodrug, it must meet three tests. It must itself be biologically inactive. It must be metabolized to a second substance in a human at a rate and to an extent to produce that second substance at a physiologically meaningful concentration. Thirdly, that second substance must be clinically effective. Determining whether a particular compound meets these three criteria in a clinical trial setting requires a large quantity of experimentation.
b) The direction concerning the prodrugs is found in the specification is limited to the definition of prodrug. So, no more than a definition of prodrug is disclosed.
c) There is no working example of a prodrug of a compound the formula (I). In the instant case, the application neither teaches how to make the claimed prodrugs nor discloses an example of a prodrug within the scope of the claims and the corresponding active compound. Therefore, the application clearly fails to provide a representative number of species of the widely divergent subject matter encompassed by the claimed prodrugs.
d) The nature of the invention is clinical use of compounds and the pharmacokinetic behavior of substances in the human body..
e) Prodrugs are commonly known in the art as drugs which are administered in an inactive (or less active) form, and then metabolized in vivo into an active metabolite. The state of the arts in prodrugs is provided by Stella (J. Pharmaceutical Sciences, 2010, 99(12), pp. 4755-4765), "So while it may appear to be straightforward to try a prodrug approach, making and identifying the best prodrugs that will work in a specific case is less than routine”, see page 4763, left-hand column. Prodrugs are drugs used to overcome some barriers to the utility of the parent drug molecule. Stella addresses the barriers in the form of questions on page 4763. These barriers include, but are not limited to, solubility, permeability, stability, presystemic metabolism, and targeting limitations. Stella also states, “I have seen in both my academic and work capacity as a consultant that what may appear to be straightforward is most often far from predictable”, see page 4763, left-hand column.
Further, the state of the prodrug art is summarized by Wolff (Burger’s Medicinal Chemistry and Drug Discovery, 5th Ed., Vol.1, 1995). The table on the left side of page 976 outlines the research program to be undertaken to find a prodrug. The second paragraph in section 10 and the paragraph spanning pages 976-977 indicate the low expectation of success. In that paragraph the difficulties of extrapolating between species are further developed. Since, the prodrug concept is a pharmacokinetic issue, the lack of any standard pharmacokinetic protocol discussed in the last sentence of this paragraph is particularly relevant. Banker (Modem Pharmaceutics, 3rd Ed., 1996) in the first sentence, third paragraph on page 596 states that “extensive development must be undertaken” to find a prodrug. A prodrug as defined by Bundgaard (see page 1 in Design of Prodrugs, 1985, chapter 1) “is an inactive species, and therefore, once its job is completed, intact prodrug represents unavailable drug” (see page 1). Thus, an important requirement of prodrugs is that they be pharmacologically inactive.
f) The artisans making Applicants' prodrugs as a collaborative team of synthetic pharmaceutical chemists and metabolism experts. All would have a Ph. D. degree and several years of industrial experience.
g) It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved", and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). h) The breadth of the claims includes all of the hundreds of thousands of compounds of formula of claim 1 as well as the presently unknown list potential prodrug derivatives embraced by claim 1.
MPEP 2164.01(a) states, “[a] conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here. Thus, undue experimentation will be required to determine if any particular derivative is, in fact, a prodrug.
The Examiner suggests deleting the term "prodrug", from claims.
Claim Rejections - 35 USC § 112(a) [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 1-23 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 1 is drawn to compound comprising a sequence of formula (I) or a tautomeric or stereochemically isomeric form thereof or a prodrug, salt or zwitterion thereof, with the recited limitations, wherein variables, viz., R1, AA1, AA2, LysR, X and Y, are represented by divergent amino acids or sub-genus chemical groups.
The term “comprising” is an open language and so, the claimed compound can have additional components in addition to the sequence of formula (1). In other words, claimed sequence of formula (1) is part of the claimed compound and so, the scope of compound is very broad or unknown.
The variables, X and Y can be adjoined to any natural or non-natural amino acid sequence or any other moiety, functional group or groups. In other words these can be any or all possible chemical groups.
Further, stereochemically isomeric form means that the compounds that differ in the chirality of one or more stereo centers, and includes enantiomers and diastereomers. In other words, it encompasses all possible isomers. The term “prodrug” and its scope is quite broad and it reads all forms of prodrugs. It can be polymer-bound prodrug, acyclic prodrugs which form heterocyclic compounds in vivo, conjugates consisting of two or more drug molecules which are cleaved into active drug molecules, amine precursors which are converted to amines in vivo, and drugs bound to a carrier via a linker. So while it may appear to be straightforward to try a prodrug approach, making and identifying the best prodrugs that will work in a specific case is less than routine.
Dependent claims further limit the variables of independent claim with the recited sub-genus species and then specific species. AA2 is defined with the recited divergent species in claims 10-12. Similarly, LysR is also defined with divergent chemical groups in claims 13-17. Only claim 21 recites species for the claimed compound. Claim 22 recites the associated property of the claimed compound.
So, based on claimed variables, the sequence of formula (1) can generate thousands of sequences in different combinations.
However, it appears that there is no defined core structure for the claimed compound or the sequence of formula (1). The core structure is responsible for the properties of individual moieties and these are associated with property of claimed compound as a whole, and in its absence of clear definition makes the invention unpredictable, and cannot be understood by a skilled person in the art.
Specification described sequences for the claimed formula in Examples 1-33, wherein R1 is limited H and phenyl ring, and no sequence is shown with heteroaryl groups; AA2 is limited to Phe, Ser, Ala, Abu and Aib, though the claimed species are very broad; LysR is limited to Lys and Lys-gammaGlu-2xOEG C18 diacid, though the claimed species are very broad; AA3 is limited to Nle; AA4 is limited to Glu; AA5 is limited Ala; AA6 is limited Arg; AA7 is limited to Ile, tBu-Ala and Val; AA8 is limited to cycloGlu; AA9 is limited to cycloLys; AA10 is limited Gly and Ala; AA11 is limited to -NH2 and Gly; AA12 is limited to Pro; AA13-AA18 are limited to Ser and AA19 is limited to -NH2. Though the claimed species for the sequence, at least based on R1, AA2 and LysR, are very large, but the described data is very limited. Functional pKb values are shown in Examples A and B with the sequences of examples 1-33 and 1-32. In Example C, effects of intravenous administration of a lead GPL1 antagonist peptide on blocking or reducing or antagonizing exendin-4 induced (GLP1 receptor agonist) improvement in glucose tolerance in lean mice, but the data is limited to Example 12 sequence.
Applicants can claim as broadly as possible for the claimed invention. However, if there is a variability in the genus or broadly claimed subject matter, and if the variability 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 invention. In this case, 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, the absence of description with 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 thousands of possible divergent sequences or compounds can be generated based on the claim language, (i) did applicants provide enough description for making all possible sequences or compounds with all possible combinations? (ii) will the generated divergent sequences or compounds be capable of retain its end property? Based on (i) and/or (ii), will a skilled person in the art understand the 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. Specification described sequences in Examples 1-32. However, claimed species for the sequence, at least based on R1, AA2 and LysR, are very large and can generate thousands of species, but the described data is very limited. So, the provided description is very limited, and no description or evidence is provided, specifically nexus between shown data and its end property. No description is provide such a way, the shown data can be extrapolated to all possible species for the claimed sequences or compounds, and the resulted ones can retain the end property.
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:
Drawings, Fig.1 and 2 are limited to single species, which is Example 12.
(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:
Though the claimed individual compounds or sequences and their synthetic methods are known, but the coupling or cross linking the with linkers are unpredictable, and this is applicable specifically to make LysR and AA2 groups. The reaction conditions for divergent moieties are expected to be different. These are in turn effect the linking chemistry. Synthetic organic chemistry is quite unpredictable. See In re Marzocchi and Horton 169 USPQ 367 3. The described synthetic methodology is very generic.
With regard to alternative amino acids in the claimed sequences, 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. 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 addition, large chemical groups present in the definitions of R1, AA2 and/or LysR, such as phenyl rings, heteroaryl groups and linker type groups can influence the properties of peptide.
In view of above evidences, applicants have claimed unlimited range of conjugates 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, and so, making it impossible for an individual of ordinary skill in the art to determine which of the very large genus of claimed sequences or compounds would retain its end property. 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.
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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