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 11/30/2022, 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 II corresponding to claims 8-15, without traverse, in the reply filed on 01/09/2026 is acknowledged.
The examiner also acknowledges applicants response to election of species and providing species for the claimed subject matter. However, to avoid delay in the prosecution, all species are examined in the elected group in this office action.
Claims 1-7, 16-17, 19 and 27-28 are withdrawn from consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.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 8-15 are examined on merits in this office action.
Claim objections
Claim 13 is objected to because of the following informalities: claim recites “animals/plants”, which is confusing because it is unclear whether the slash stands for “and”, “or” or “and/or”. 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 8-15 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:
The independent claim 8 is drawn a drug conjugate comprising:
a first unit drug conjugate; and
a second unit drug conjugate that is capable of being bound to the first unit drug conjugate in vivo,
wherein the first unit drug conjugate comprises a first binding group, a first target substance that specifically binds to target cells, and a first drug; and
the second unit drug conjugate comprises a second binding group that binds to the first binding group of the first unit drug conjugate.
In the above independent claim, all are variables. Each variable is associated with the recited property. There are no limitations on any claimed variable. In other words, claimed drug conjugate can comprises all possible drugs, which can be organic compound or a peptide or a nucleic acid, first and second binding group can be any chemical group, target substance can be also any chemical group that can bind to all possible target cells.
Dependent claims 9-11 define the interaction between first binding group and second binding group with the recited reactions.
Dependent claim 12 defines second unit drug conjugate but very broadly.
Dependent claim 13 provides laundry list for the first drug, and all are divergent compounds. The recited radioisotopes and dye compounds are not even drugs.
Dependent claim 14 defines first target substance binds to target generically.
Dependent claim 15 further defines second unit drug conjugate, but generically
In the above dependent claims, all are variables and each variable is associated with the recited property. There are no limitations on any claimed variable.
The claimed subject matter can generate unlimited number of drug conjugates. No claim recite species for claimed drug conjugate or any of claimed variable. Claims do not even characterize the structural features of any variables. In other words, claims are written in a quiz language. This is not the proper way to write the claims.
It is clear from the above, that there is no defined core structure for the claimed drug conjugate or not even a core structure for any variable for the broadly claimed subject matter. The core structure is responsible for the properties of individual variables and these are associated with property of claimed variables and the conjugate 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.
To support the above claimed subject matter, specification exemplified the binding affinity for drug conjugate 6-7, which is combination of unit drug conjugates 6 and 7, and drug conjugate 13-14, which is assumed to be a combination of 13 and 14, since its structure is not shown in the disclosure. The observed IC50 is 0.52 nM for drug conjugate 6-7 and 69.7 nM for drug conjugate 13-14, which is huge difference in the binding property. It appears that these two conjugates are tested in a single cell lines, U-87MG cells. In the tested drug conjugates, the target substance is limited to RGD peptide A and B, binding group is ADIBO and azide, drug is iodine and linker is Asp. No description is provided on how the shown data is extrapolated to claimed all possible drug conjugates.
So, the issue is in the scope of the broadly recited variables in the claimed drug conjugate. 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, at least the properties of target substance, which can be an organic compound or peptide, and linker, which can link target substances, unpredictable, since 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. That means the specification failed to describe the core structure responsible for its activity, in other words, the structure/function relationship for the claimed generic drug conjugate is not described.
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 unlimited drug conjugates can be generated from the claimed subject matter, (i) did applicants provide enough description for making all possible conjugates with all possible targeting substances, linkers, binding groups and drugs etc.? (ii) will the resulted drug conjugates be capable of retain its property? Based (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. Claimed drug conjugates comprises target substances, drug(s), binding groups, wherein target substances are linked through a linker.
Specification generically or theoretically described unit drug conjugates and their structural features, wherein target substance is limited to RGD peptide and linker is limited to Asp.
Shown data is limited to two drug conjugates, viz., drug conjugate 6-7, which is combination of unit drug conjugates 6 and 7, and drug conjugate 13-14, which is assumed to be a combination of 13 and 14, since its structure is not shown in the disclosure. Both shown conjugates are limited to RGD peptide A and B as a target substance, ADIBO and azide as binding group, drug is iodine and linker is Asp. No data is shown with another other variables. No description is provided on how the shown data is extrapolated to all possible drug conjugates. Moreover, the observed IC50 is 0.52 nM for drug conjugate 6-7 and 69.7 nM for drug conjugate 13-14, which is huge difference in the binding property and limited single cell lines U-87MG cells.
Specification also exemplified IC50 values for unit drug conjugates 1, 2, 1-2, 7, 12a, 12b, 12c, 13 and 14 in the Table 2, but these are not relevant to the claimed subject matter, because when these are conjugated to a drug conjugate, the resulted drug conjugate may or may not retain its property, in absence of description in the specification.
Preparative methods in the disclosure are also limited to RGD peptides for target substance, and preparative methods may be different if target substance is organic compound or antibody etc.
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 describe verification of crosslinking between unit drug conjugates,
but the description is limited to drug conjugates 1-2 and 3-4. Verification of in vivo binding affinity and cellular internalization of drug conjugates 1-2 and 3-4 are shown in Fig.3. Drug conjugate 5-6 is tested in different tumors, as shown in Fig.4-6, but these showed very divergent properties.
In all the described drug conjugates in the drawings, target substance is limited to RGD peptides, linker is limited to Asp, binding group is limited ADIBO and azide etc.
(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 synthetic methods for the drug conjugates in the shown data are known in the art, but the coupling or cross linking various target substances with all possible linkers are unpredictable. The reaction conditions for small target substances are expected to be different for big target substances. These in turn effect the coupling or cross 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.
If target substance is peptide, and claimed target substance reads all possible peptides, which can have all possible combination of amino acids in their 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.
With regard to linkers, the properties of conjugates are sensitive to the linker moiety [see section 6 in He et al, Molecules, 2019, 24, 1855, 1-34; see abstract and conclusion in Lu et al, International Journal of Molecular Sciences, 2016, 17, 561, 1-22].
The art also recognizes that the choice of a linker has great impacts on biological activity, expression yield, and pharmacokinetic properties of a fusion partner (see Chen et al. Adv. Drug Deliv. Rev. 65:1357-1369, 2013).
Verdine et al (Methods in Enzymology, 2012, vol.503, 3-33) also showed or described possible unpredictability in staples in the peptide conjugates [see sections 3-5 and 13-14].
In view of above, applicants have claimed unlimited range of conjugates and these conjugated are linked to a specific property, and so, 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 conjugates would be effective in retaining the desired 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