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 .
Election/Restrictions
The election of the IL-2 polypeptide of SEQ ID NO: 28 in the remarks filed 03/17/2025 is acknowledged. Claims 4 and 6-8, and 34 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 1, 2, 11, 13, 15, 17, 20-22, 24-27, 42, and 43 are examined here upon their merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The instant application claims the benefit of 63/219,995 filed 07/09/2021 and 63/219,989 filed 07/09/2021. All claims examined here on their merits are given the benefit of 63/219,995 and are granted a filing date of 07/09/2021.
Information Disclosure Statement
The information disclosure statement filed 03/18/2025 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered.
The information disclosure statement(s) (IDS) submitted on 08/04/2023 and 03/18/2025, with the exception of foreign patent documents 002 and 003, follow the provisions of 27 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
The disclosure is objected to because of the following informalities:
Table 3 of the specification filed 02/27/2023 is incomplete in that the polymer structure for each of formulas A-D are not shown. The polymer structure for formula E appears to be incomplete.
Table 3 lists polymer identifiers and the corresponding polymer structure. Table 4 lists linker identifiers and the corresponding linker structure. Both tables use the naming convention of Formula A, B, C, etc. In fact, both tables refer to Formulas A-E. Referring to table 3 from the specification filed 07/09/2022, it is clear that said linker and polymer structures labelled Formulas A-E are not the same structure. As a result, there are five instances in which two structures have the same label.
Appropriate correction is required.
Claim Objections
Claim 1 is objected to because of the following informalities:
Claim 1 recites “a modified interleukin-2 (IL-2) polypeptide, comprising: a modified IL-2 polypeptide” which is redundant
Claim 26 recites “… IL-2 polypeptide claim 1 …” which should read “… IL-2 polypeptide of claim 1 …”
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.
Claims 1, 2, 11, 13, 15, 17, 20-22, 24-27, 42, and 43 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.
It is unclear if the modified IL-2 polypeptide of claim 1 comprises a polymer. Claim 34 recites the modified IL-2 polypeptide of claim 1 wherein the modified IL-2 polypeptide comprises the sequence set forth in SEQ ID NO: 3. The sequence listing of SEQ ID NO: 3 notes that glutaric acid and .5kDa azido polyethylene glycol-alanine is attached to site 1. Claim 34 depends directly upon claim 1 and the presence of a polymer attached to a polypeptide as claimed implies that claim 1 allows for a polypeptide with an attached polymer.
There are, however, several instances which contradict this indication. For example, Composition A is referred to as an unconjugated IL-2 and Composition A1 is referred to as a PEGylated IL-2. Composition A, however, is defined as SEQ ID NO: 3 which comprises a polymer, supra attached at residue 1. Furthermore, table 6 and several other places within the instant specification recite sequences as in SEQ ID NOs: 4-8 + 0.5kDa azido PEG. SEQ ID NOs: 4-8, however, already contain a glutaric acid and .5kDa azido polyethylene glycol-alanine and there is no reference to a second 0.5kDa azido PEG being attached
For the sake of compact prosecution, the examiner has examined claim 1 of the instant disclosure as not comprising a polymer.
The term “about” in claims 25-27 is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The instant specification paragraph [0039] fails to provide a specific definition for the term “about” or “approximately”. The paragraph specifies that “about” may mean within or more than 1 standard deviation. The paragraph further recites that “about” can mean a range up to 1% or up to 20% or within an order of magnitude, within 5-fold, or within 2-fold of a value. The definition of the terms “about” or “approximately” as provided in the instant specification does not provide one of ordinary skill in the art enough information to determine the scope of the claims.
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, 2, 11, 13, 15, 17, 20-22, 24-27, 42, and 43 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.
Claim 1 is directed to a modified IL-2 polypeptide comprising up to seven natural amino acid substitutions which comprise amino acid substitutions at residues Y31, K35, and Q74 as referenced in instant SEQ ID NO: 1. Paragraph [0023] of the instant specification recites that modified IL-2 polypeptides contain modified amino acid residues such as amino acid substitutions, addition or deletion of amino acids, or the addition of moieties to amino acid residues. Paragraph [0025] of the instant specification specifies that the modified IL-2 polypeptide may comprise unnatural (non-canonical) amino acids, of which there are dozens.
Claim 1, therefore, encompasses an exceedingly large number of species with no requirement for length, structure, or sequence. The specification teaches that the modified IL-2 polypeptide exhibits a binding affinity for the IL-2Rα subunit between about 0.1 nM and 100 nM, and a binding affinity for the IL-2Rβ subunit which is at least about 1000 nM (instant specification paragraph [0006]). Applicant has described the use of several IL-2 muteins, however, the described muteins represent a small portion of sequences which are encompassed by claim 1. The claims do not require that the recited variant of IL-2 possesses any particular conserved structure, length or sequence. The disclosure of the sequences as described in tables 1-3 do not adequately describe the scope of the genus of the encompassed variants of IL-2 that maintain the desired property of a binding affinity for the IL-2Rα subunit between about 0.1 nM and 100 nM, and a binding affinity for the IL-2Rβ subunit which is at least about 1000 nM.
To provide adequate written description and evidence of possession of a recited genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In this case, the only factor present in the claims is a reference sequence of IL-2 and a small number of identified mutations of said sequence. There is no identification of any particular sequence portion of the variant IL-2 that must be conserved, in order to retain the desired property of a binding affinity for the IL-2Rα subunit between about 0.1 nM and 100 nM, and a binding affinity for the IL-2Rβ subunit which is at least about 1000 nM.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that “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). As discussed above, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus of IL-2 variants, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class as the specification provided only the bovine sequence.
Therefore, applicant has not disclosed sufficient species or common structural features such that one skilled in the art would conclude that applicant was in possession of the claimed genus of IL-2 polypeptides (including variants and fragments thereof). Therefore, only the IL-2 polypeptide comprising the amino acid sequences of SEQ ID NOs: 1-43, but not the full breadth of the claims meets the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AlA), first paragraph.
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Claims 1, 2, 11, 13, 15, 17, 20-22, 24-27, 42, and 43 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 the sequences of instant SEQ ID NOs: 1-43, does not reasonably provide enablement for a modified IL-2 polypeptide, wherein the modified IL-2 polypeptide comprises up to seven natural amino acid substitutions comprising substitutions at residues Y31, K35, and Q74. 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 the invention commensurate in scope with these claims.
The instant claims encompass a modified IL-2 polypeptide comprising up to seven natural amino acid substitutions comprising substitutions at residues Y31, K35, and Q74. The modified IL-2 polypeptide may comprise natural amino acid substitutions, unnatural amino acid substitutions, amino acid insertions, and amino acid deletions. Thus, the claims do not encompass polypeptides that comprise sequences of any particular length, sequence, or structure. Claims 25-27 teach that the modified polypeptide of claim 1 exhibits a binding affinity for IL-2Rα between about 0.1 nM and about 100 nM and a binding affinity for IL-2Rβ of at least about 1000 nM. However, the claims encompass variants of IL-2 that may vary substantially in length and also in composition, with no requirement for any particular structural feature or function. The claims do not require that the recited variants of IL-2 possess any particular conserved structure, or other disclosed distinguishing feature. The specification teaches variants of IL-2 that retain the activity of a binding affinity for IL-2Rα between about 0.1 nM and about 100 nM and a binding affinity for IL-2Rβ of at least about 1000 nM (see Figure 5). The disclosure of variants of IL-2 that demonstrate the appropriate binding affinity for IL-2Rα and IL-2Rβ, does not enable the scope of the genus of the encompassed variants of IL-2 that maintain the desired activity of the claimed binding affinity. While recombinant techniques are available, it is not routine in the art to screen large numbers of polypeptides that might potentially retain the desired activity, because the expectation of obtaining similar activity is unpredictable.
Thus, one of skill in the art would require additional guidance, such as information as to what structural features would result in the variants or fragments of the claimed peptide which retain the desired activity. Thus, to practice the invention commensurate with the scope of the claims would result in undue experimentation.
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. While it is known that many amino acid substitutions are generally possible in any given protein the positions within the protein's sequence where such amino acid substitutions can be made with a reasonable expectation of success are limited. Certain positions in the sequence are critical to the protein's structure/function relationship, e.g. such as various sites or regions directly involved in binding, activity and in providing the correct three-dimensional spatial orientation of binding and active sites. These or other regions may also be critical determinants of antigenicity. These regions can tolerate only relatively conservative substitutions or no substitutions. However, Applicants have provided little or no guidance beyond the mere presentation of sequence data to enable one of ordinary skill in the art to determine, without undue experimentation, the positions in the protein which are tolerant to change (e.g. such as by amino acid substitutions or deletions), and the nature and extent of changes that can be made in these positions. Although the specification outlines art-recognized procedures for producing and screening for active muteins, this is not adequate guidance as to the nature of active derivatives that may be constructed, but is merely an invitation to the artisan to use the current invention as a starting point for further experimentation. Even if an active or binding site were identified in the specification, they may not be sufficient, as the ordinary artisan would immediately recognize that an active or binding site must assume the proper three-dimensional configuration to be active, which conformation is dependent upon surrounding residues; therefore substitution of non-essential residues can often destroy activity. The art recognizes that function cannot be predicted from structure alone (Bork, 2000; Skolnick et al., 2000, especially p. 36 at Box 2; instant PTO-892). Tokuriki et al. 2009 (instant PTO-892) also teaches that mutations are generally destabilizing. For instance, Tokuriki teaches at p. 596, right column, last paragraph, that “as mutations accumulate, protein fitness declines exponentially...or even more than exponentially...So by the time an average protein accumulates, on average, five mutations, its fitness will decline to <20%.” Further, at p. 598, left column, last paragraph, Tokuriki notes that 50% of mutations are destabilizing, and >15% of mutations are highly destabilizing, and of the about 5% of mutations that are stabilizing values... many of these mutations result in inactive protein. Tokuriki concludes that “a more comprehensive understanding of how mutations affect protein fitness within living cells is needed, including their combined effects on function, thermodynamic and kinetic stability, and clearance through aggregation and degradation” (see p. 602, left column, 2nd paragraph), thus underscoring the lack of predictability with regard to the effects of mutation on protein function in vivo. In conclusion, Tokuriki teaches that “[mJutations, and mutations that alter protein function (new-function mutations), in particular, are generally destabilizing, and can reduce protein and organismal fitness.” (See p. 602, left column, 2nd paragraph).
The criteria set forth in Ex parte Forman (230 USPQ 546 (Bd. Pat. App. & Int. 1986), and reiterated in In re Wands (858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)), which include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art and (8) the breadth of the claims, is the basis for determining undue extermination. In the instant case, one skilled in the art would not be able to predict which variants of IL-2 would maintain the desired activity of a binding affinity for IL-2Rα between about 0.1 nM and about 100 nM and a binding affinity for IL-2Rβ of at least about 1000 nM. Finally, due to the large quantity of experimentation necessary to generate the hundreds of IL-2 variants recited in the claims and screen the same for activity; the lack of direction/guidance presented in the specification regarding which structural features are required to provide activity for the claimed variants; the complex nature of the invention; and the state of the prior art which establishes the unpredictability of the effects of mutation on protein structure and function, the skilled artisan would not know how to make and use the invention recited in claims 1, 2, 11, 13, 15, 17, 20-22, 24-27, 42, and 43 in its full scope.
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 (i.e., changing from AIA to pre-AIA ) 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, 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 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, 11, 13, 15, 17, 21, 22, and 24-27 are rejected under 35 U.S.C. 103 as being unpatentable over Gavin US-20140286898-A1 (hereafter Gavin).
Instant claims 1, 2, 11, 13, 15, 17, 21, 22, and 24-27 are drawn to a modified IL-2 polypeptide.
Gavin teaches a protein comprising an IL-2 mutein (Gavin claim 110) which consists of an amino acid sequence identical to the reference sequence of instant SEQ ID NO: 1 with 4 natural amino acid substitutions (Gavin SEQ ID NO: 10). Said substitutions are K35R, V69A, Q74P, N88D, and C125A. Gavin further teaches the use of a known Y31H substitution which confers to IL-2 a high affinity for CD25 (IL-2Rα) (Gavin specification page 32 lines 29-35). SEQ ID NO: 10 contains a substitution at C125 and teaches that this substitution is added to prevent cytosine mispairing and aggregation and that a substitution of serine is a common choice (Gavin specification page 32 lines 32-33). Gavin further teaches that the residue of C125 may be substituted with a number of amino acids, including serine (Gavin SEQ ID NO: 1). Gavin SEQ ID NO: 10 is described as synthetic in the sequence listing of Gavin. Gavin does not recite the binding affinity of Gavin SEQ ID NO: 10 for IL-2 Rα but does describe the binding affinity of similar sequences such as Gavin SEQ ID NO: 14 and instant SEQ ID NO: 1 with the substitutions of V69A and Q74P. Gavin describes the binding affinity of said muteins as .2 and 2 nM, respectively. Furthermore, structure begets function and so the sequence as made obvious by Gavin must also have an identical binding affinity for IL-2 Rα and IL-2Rβ as the instantly claimed sequence. Gavin, therefore teaches instant claims 1, 2, 11, 13, 15, 17, 21, 22, and 24-27.
Claims 42 and 43 are rejected under 35 U.S.C. 103 as being unpatentable over Gavin as applied to claim 1 above, and further in view of Krantz WO2019090242 (hereafter Krantz) and Alas M., et al. J Med Chem. 2021 (hereafter Alas).
Instant claims 42 and 43 are drawn to the modified IL-2 polypeptide further comprising a conjugation handle.
Gavin teaches the linking of nonproteinaceous polymers such as polyethylene glycol to the IL-2 mutein of Gavin. Gavin also teaches that the pegylated proteins may have increased half-life and/or reduced immunogenicity over the non-pegylated proteins (Gavin specification page 15, lines 30-32). Gavin is silent on the specific addition of a conjugation handle to the IL-2 polypeptide claimed supra as well as the attachment of a glutaric acid and azido PEG to the N terminus of said polypeptide as described in instant claims 42 and 43. Krantz and Alas remedy this deficit. Krantz teaches the attachment of azido-PEG molecules to several proteins (Krantz compounds B, C, and G-J) and Alas teaches that glutaryl linkers are commonly used to conjugate peptides to polymers (Alas section 2.1 Ester and Amide). It would have been obvious to combine the linker of Alas with the PEG molecule of Krantz because both were used at the time of filing to achieve desired changes in polypeptides.
Double Patenting
A rejection based on double patenting of the “same invention” type finds its support in the language of 35 U.S.C. 101 which states that “whoever invents or discovers any new and useful process... may obtain a patent therefor...” (Emphasis added). Thus, the term “same invention,” in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957).
A statutory type (35 U.S.C. 101) double patenting rejection can be overcome by canceling or amending the claims that are directed to the same invention so they are no longer coextensive in scope. The filing of a terminal disclaimer cannot overcome a double patenting rejection based upon 35 U.S.C. 101.
Claims 1, 2, 11, 13 and 15 are provisionally rejected under 35 U.S.C. 101 as claiming the same invention as that of claims 1 and 5 of copending Application No. 17861178 (hereafter ‘178) (reference application). This is a provisional statutory double patenting rejection since the claims directed to the same invention have not in fact been patented.
Claim 1 of ‘178 recites a modified IL-2 polypeptide comprising amino acid substitutions Y31H, K35R, and Q74P based upon a sequence identical to instant SEQ ID NO: 1. Claim 5 of ‘178 further recites that said modified IL-2 polypeptide comprises an additional amino acid substitution at N88D. These claims therefore encompass the limitations of instant claims 1, 2, 11, 13 and 15.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KATRINA J CAMPBELL whose telephone number is (703)756-1326. The examiner can normally be reached Monday - Thursday 7:30 - 5 (ET), Every other Friday 7:30 - 4 (ET).
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/KATRINA J. CAMPBELL/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675