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 .
Status of the application
Receipt of applicant’s remarks and claim amendments filed on 06/23/2026 are acknowledged.
However, applicants’ arguments for the previous 112(a) written description rejection are found not persuasive. In light of claim amendments, which changes scope of claimed subject matter, accordingly, the rejection is modified.
Response to Arguments
(i) Applicants’ argue that any variant that fails to bind serum albumin is excluded from the claim regardless of its sequence identity score. Albumin binding is a concrete, measurable property - readily assessed by surface plasmon resonance (SPR) or biolayer interferometry (BLI) using standard assays.
In fact, some of the claimed sequences, as shown in Table 1, do not bind to serum albumin. In addition, no evidence is shown for the properties of 90% identity sequences, though 10% or less expected to change the property of claimed sequences, as explained in the written description with evidences.
(ii) Applicants argue that the specification discloses 40 specific VHH sequences (SEQ ID NOS: 1-37 and 124-126), each set forth in full in the sequence listing. The specification further discloses 15 conjugate compounds (SEQ ID NOS: 100-118) combining those VHH sequences with diverse biotherapeutic payloads (CNTF, NRG1, GDF15, IL-2, GLP-1, and Fab fragments).
Main issue is no evidence is shown for the properties of 90% identity sequences, though 10% or less expected to change the property of claimed sequences. Further, some of the claimed sequences, as shown in Table 1, do not bind to serum albumin. Claim 1 and 56 do not require conjugate forms, because the claimed compound(s) minimally represented by SEQ ID NOs:1-37 and 124-126 and remaining is optional.
(iii) Applicants argue that the specification discloses a clear correlation between VHH sequence, albumin binding, and half-life extension. Tables 1-10 quantify albumin binding affinities for the disclosed sequences. Examples 19-23 demonstrate in vitro activity of VHH-biotherapeutic fusions. Examples 25-28 demonstrate in vivo activity. Examples 29-31 demonstrate extended pharmacokinetic profiles, directly linking albumin-binding VHH structure to t1/2 extension function.
Claimed compound(s) minimally represented by SEQ ID NOs:1-37 and 124-126 and remaining is optional. As explained above, some of the claimed sequences, as shown in Table 1, do not even bind to serum albumin. In addition, no evidence is shown for the properties of 90% identity sequences, though 10% or less expected to change the property of claimed sequences. Shown data is limited fusion proteins and conjugates, but these are optional in claims 1 and 56.
Claim Objections
Claim 56 is objected to because of the following informalities: claim does not depend on independent claim or any other claim, nor it is an independent claim. 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 and 56 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 a compound comprising an amino acid sequence selected from the group consisting of SEQ ID NOS:1-37 and 124-126, or at least about 90% sequence identity thereto, wherein the compound binds serum albumin. Dependent claim 56 is drawn to a compound of claim 1 for use in extending the t1/2 of a biotherapeutic.
In the claims, the term “comprising” is an open language and does not exclude other components in the claimed compound. In other words, claimed compound may or may not have other components in it or claimed compound can be simply represented by SEQ ID NOs: 1-37 and 124-126, and nothing else. So, claimed sequences [SEQ ID NOs: 1-37 and 124-126 or at least about 90% sequence identity thereto] are nothing but claimed compound(s), and these ranges from 126 to 128 amino acids length. The remaining 10% of these sequences is about 12-13 amino acids, and these can be any amino acids. For example, all can be negatively or positively charged or hydrophobic or all can be prolines or cysteines etc.
Claimed compounds are associated with (i) serum albumin binding properties, and (ii) extending the t1/2 of a biotherapeutic. According to specification, the term "biotherapeutic" and the like means an amino acid- or nucleic acid-based compounds such as antibodies, coagulation factors, clotting factors, cytokines, enzymes, growth factors, hormones, and fragments thereof, having at least one therapeutic activity/applicability, as well as therapeutic DNA and/or RNA molecules.
In addition, according to specification, compounds can include other sequences, which are coupled to the claimed sequences [recited sequences in claim 1] through a linker sequences.
To support above claimed subject matter, specification describes SEQ ID NOs: 3-4, 8-27 and 125-16 and properties towards serum albumin in Table 1. It appears that some of the sequences labeled as “no binding”. No evidence is shown that these sequences have the property of extending the t1/2 of a biotherapeutic. Moreover, biotherapeutic is very divergent.
Further, specification describes that a single domain antibodies known as variable domains of heavy chain-only antibodies (VHH) that are engineered/modified to act as half-life (t%/)-extending moieties for use with therapeutic agents, especially for improving t1/2 of biological-based therapeutic agents (i.e., biotherapeutics or biologics). But these are in the conjugate or fusion form of proteins. So, the claimed sequences in form of fusion proteins or conjugates show the property of extending the t1/2 of a biotherapeutic, not as in the individual form. Moreover, claims do not require fusion proteins or conjugates.
In the specification, shown evidences are limited to fusion proteins, represented by SEQ ID NOs:100-118. Binding of some of claimed sequence in claim 1 with serum albumin are shown in Tables 1. All examples are limited to fusion proteins and conjugates, specifically, in vitro potency of VHH-based fusion proteins. However, specification does not describe or exemplify the properties of claimed sequences towards extending the t1/2 of a biotherapeutic. No description is provided with sequences having 90% identity of claimed sequences.
In light of above, (i) did applicants provide enough description for making sequences of 90% of sequences identity and remaining can be any possible amino acids with all possible combinations, and (ii) will these be capable of retain its property for serum albumin and retain properties towards extending the t1/2 of a biotherapeutic? Based (i) and/or (ii), will a skilled person in the art understand the claimed invention?
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.
(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 compound(s) are minimally represented by SEQ ID NOs: 1-37 and 124-126 and the properties of these sequences towards extending t1/2 of a biotherapeutic are not described or not shown.
All the provided description in the specification is limited to conjugates consisting of albumin binding domain, linker sequences and claimed sequences of claim 1.
In Table 1, did not show all claimed sequences, but shown sequences have divergent properties and some of these did not even bind to serum albumin. If remaining 10% is divergent sequences, then the resulted sequences may have different properties. No description is provided for these sequences.
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:
No diagrams are Figures are shown in the specification.
(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:
At least, in the claimed sequences, which can have 10% all possible combination of amino acids in their sequences, 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 the claimed compound(s), if claimed sequences are coupled to other sequences through linker sequences, as described in the specification, then 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, 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 compounds or conjugates would be effective in retaining their end properties. 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
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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
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