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 .
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.
DETAILED ACTION
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/24/2025 has been entered.
Claims 1, 3, 4-5, 9-11, and 26-35 were amended. Claim 6 was canceled.
Claims 1-5 and 9-58 are pending in the instant application.
Priority
This application is a 371 of PCT/US2019/033100, filed on 5/20/2019 which claims priority to the provisional application 62674244 filed on 5/21/2018.
Election/Restriction
Applicant’s election without traverse of Group I, claims 1-42 in the reply filed on 9/23/2024 remains in effect. Claims 43-58 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group, there being no allowable generic or linking claim.
Claims 1-5, 9-42
Claims 1-5 and 9-42 are examined herein.
Claim Interpretation
In response to the request for information in the restriction mailed on 3/22/2024, applicant clarified that the description of “tri-PEGylated” IL-2, refers to structure N, as opposed to structure S, where the “tri” specifically refers to the quantity of attachments to IL-2, a.k.a. variable n’.
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200
400
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Greyscale
In the remarks posted on 12/24/2025, applicant clarified that the mole percentages are based on the total number of PEGylated IL-2 conjugates. Thus claim 1 was interpreted as a mixture of n’ = 1, 2, or 3, wherein a third PEGylated IL-2 conjugate, not of formula 1 (labeled “F”) is invoked so that the mole percentages sum to 100%.
n’
lowest mol%
highest mol%
1
0
5 - 5.25
2
26.6 - 28
60 - 63
3
22.8 - 24
65 - 68.25
sum
49.4 - 51.87
F
50.6 - 48.13
For example, if there is 5% n’ = 1, 60% n’ = 2, and 24% n’=3, then F has a mol% of 11%, so that the sum of all these mol % is 100%. Any compositions that sum in excess of 100% are not valid interpretations of the claim.
Applicant refers to “higher PEGylated IL-2” in claims 26, 28, 30, 32, and 34. This was interpreted as n’ being greater than four, using the detailed description which recites:
“Compositions provided herein comprise selected mixtures of IL-2 PEG conjugates having defined fractions of predominantly di-PEGylated and tri-PEGylated IL-2, and defined lesser fractions of mono-PEGylated IL-2, and/or tetra or higher PEGylated IL-2.”
Objections to the Claims
Claim 1 is drawn to “n’ is 1 and 2 and 3;” wherein applicant intends these options in the alternative. Please replace with “n’ is selected from 1, 2, or 3;”.
Correction is required. See MPEP § 608.01(m).
Claim Rejections – 35 USC § 112(b)
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 3-5 and 9-11 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.
Claim 3-5
Claims 3-5 are drawn to the composition further comprising a formula (that lacks a name) that is identical in structure to formula (I), but uses different variable definitions for n’. One of skill in the art would not be able to distinguish a formula comprising formula (I) wherein n’ = 1, and a formula that “further comprises the formula” of claims 3-5 wherein n’ = 1. Applicant may overcome this rejection by assigning different variables to the different formulas so that one is apprised of the metes and bounds of the claim (e.g. use a' in place of n’ in claim 3, use b’ in place of n’ for claim 4, use m’ in place of n’ for claim 5, etc). Alternatively, applicant could modify the base claim so that n’ can comprise values other than 1, 2, or 3; thus avoiding the unnecessary reiteration of the same formula with varying variables. See “Claim Interpretation” above for suggestions.
Claim 3-5
Claims 3-5 are drawn to the composition further comprising a formula that is identical in structure to formula (I), but uses different variable definitions for n’. Applicant has invoked different interpretations for the same variable: In one formula, n’ = 1, 2, or 3; whereas in another formula n’ = 1, 4, 5, or >5. Because there are multiple interpretations for the same variable, these claims are rendered indefinite. Dependent claims 9-11 fail to cure these deficiencies, thus are also rendered indefinite.
Claim Rejections – 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 3-5, 9-11, 26, 28, 30, 32-33, and 34-35 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 3-5
Claims 3-5 are drawn to compositions comprising mol% values for the n’ = 1 species that are in excess of 5.25%. This is due to the formula of the parent claim being identical to the formula in these child claims. For example claims 3-5 encompass adding an additional 20% of the n’ = 1 species to the formula, which expands the scope of the composition beyond the upper limit of 5.25% of n’ = 1 species in parent claim 1.
Claims 9-11
Claims 9-11 are drawn to compositions comprising n’ being greater than 3, wherein base claim 1, limits n’ to being limited to 1, 2, or 3. Thus claims 9-11 represent an expansion of scope over parent claim 1. This is due to applicant using two different formulas with the same variable names.
Claim 26, 28, 30, 32-33, and 34-35.
Claims 26, 28, 30, 32, and 34 are drawn to compositions comprising “higher PEGylated IL-2 conjugates”. Applicant has defined “higher PEGylated IL-2 conjugates” as possessing n’ > 4. (See “Claim Interpretation” section for details). Because parent claim 1 is limited to n’ being 1, 2, or 3, this represents an expansion of scope over parent claim 1. This is due to applicant using two different formulas with the same variable names. Dependent claims 33 and 35 fail to cure these deficiencies, thus are also rejected.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections – 35 USC § 103
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.
Claims 1-5 and 9-42 are rejected under 35 U.S.C. 103 as being unpatentable over Bossard et al. (WO2012065086) in view of Dai et al. (US20110166319).
*claim 1
Regarding claim 1, Bossard teaches a composition comprising a PEGylated IL-2 of the structure below (pg 32, para 0127).
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140
756
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Greyscale
Bossard teaches instant variable n is 2-4000 and instant variable n’ is 1 (pg 32, para 0127). Bossard teaches instant variable n’ can also be 2 or 3 (pg 48, para 0155, Fig 9; Example 12). Bossard teaches at least 85% of the conjugates will have 1-4 PEG polymers attached, whereas 95% will have 1-5 PEG polymers attached (pg 46, para 0150). Bossard teaches a method of generating a mixture of mono-, di-, tri-, tetra, etc- variants of the 20kDa PEGylated IL-2 (Example 4), wherein the area under the curve is respective of mol%, as can be seen in Fig 4.1 (reproduced below), Bossard teaches generating a mixture that comprises in a 1:1:1 ratio, (mono- and di-):(tri-):(tetra-) variants respectively, such that Bossard teaches ~0-28% mono; ~0-28% di, ~28% tri, ~29% tetra, 10% penta-, and 5% hexa- and above.
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media_image3.png
747
1121
media_image3.png
Greyscale
Thus the composition of Bossard has been tabulated below in comparison with the instant claims, and that of instant formula RUR20kD-IL-2, which is the sole formula referred to in the instantly supplied examples.
n’
Instant claim 1, 3
“about” instant claim 1, 3*
Instant RUR20kD-IL-2**
Bossard***
Mono-PEG
0-5
0 - 5.25
3.0
0 - 28
Di-PEG
28-60
26.6 - 63
42.4
0 - 28
Tri-PEG
24-65
22.8 - 68.25
46.6
28
Tetra-PEG
0-20
0 - 21
7.5
29
Penta-PEG
0-20
0 - 21
0.28 -0.72
10
≥6 PEG
0-20
0 - 21
0-0.22
5
*applicant defined “about” as equivalent to ±5%, which has been calculated into these ranges.
**values taken from instant Table 3. Standard deviation for 1-5 PEG’s was less than 4% thus these ranges were omitted, whereas that for 6-PEG was substantially higher (e.g. 44%), thus was calculated in the table above.
***The sum of mono + di cannot exceed 28.
Thus Bossard teaches the composition of PEGylated IL-2 variants with sufficient specificity to render obvious the instantly claimed ranges. See MPEP § 2144.05(I). Absent any evidence of criticality of these particular ratios, the composition is a matter of routine experimentation. See MPEP § 2144(III) and § 2144.05(II)(A).
claim 2
Regarding claim 2, Bossard teaches the IL-2 is aldesleukin (pg 67, para 0231).
*claim 3-5
Regarding claims 3-5, Bossard teaches an exemplary mixture comprising 0-28 mol% mono-PEG, 0-28% di-PEG, 28 mol% tri-PEG, 29 mol% tetra-PEG, 10 mol% penta-PEG, and 5 mol% hexa-PEG (Fig 4.1). Because claims 3-5 encompass “no more than 10 mol% of the mixture can comprise a hexa-PEG, this mixture of Bossard satisfies the claim limitation because it contains 5 mol% hexa-PEG (thus satisfying claims 3-5) and comprises 0-28 mol% mono-PEG (thus encompassing 0-5 mol%), 0-28 mol% di-PEG (thus overlapping 28-60 mol%), 28% tri-PEG (thus is within 24-65 mol%), as described in parent claim 1 (see Table above). Thus Bossard teaches the composition of PEGylated IL-2 variants with sufficient specificity to render obvious the instantly claimed ranges. See MPEP § 2144.05(I). Absent any evidence of criticality of these particular ratios, the composition is a matter of routine experimentation. See MPEP § 2144(III) and § 2144.05(II)(A). Bossard further teaches:
“Control of the desired number of polymers for any given moiety can be achieved by selecting the proper polymeric reagent, the ratio of polymeric reagent to the IL-2 moiety, temperature, pH conditions, and other aspects of the conjugation reaction” (pg 48, para 0153). Bossard also teaches “For example, the polymer-lL-2 moiety conjugates can be purified to obtain/isolate different conjugated species. Specifically, the product mixture can be purified to obtain an average of anywhere from one, two, three, four, five or more PEGs per IL-2 moiety, typically one, two or three PEGs per IL-2 moiety. The strategy for purification of the final conjugate reaction mixture will depend upon a number of factors, including, for example, the molecular weight of the polymeric reagent employed, the particular IL-2 moiety, the desired dosing regimen, and the residual activity and in vivo properties of the individual conjugate(s).” (pg 48, para 0154).
In the absence of evidence of criticality, compositions comprising different ratios PEGylated IL-2’s are a matter of user preference, and within the abilities of a person of skill in the art to generate.
*claim 9-11
Regarding claims 9-11, Bossard teaches multiple exemplary formulas Fig 4.1, as indicated by the shaded areas for the peak representing the 4-mer species (equivalent to n’ = 4), which have been estimated in the Table below (Fig 4.1).
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811
1319
media_image4.png
Greyscale
n’
claim 9-11
“about” claim 9-11
Instant RUR20kD-IL-2**
line 1
mol%
line 2
mol%
line 3
mol%
line 4
mol%
Mono-PEG
0-5
0 - 5.25
3.0
0-28
0-54
0-64
0-34
Di-PEG
28-60
26.6 - 63
42.4
0-28
0-15
0-64
0-34
Tri-PEG
24-65
22.8 - 68.25
46.6
28
16
5
42
Tetra-PEG
5-10
4.75 – 10.5
7.5
29
18
16
9
Penta-PEG
0-20
0 - 21
0.28 -0.72
10
10
10
10
≥6 PEG
0-20
0 - 21
0-0.22
5
5
5
5
In line 4, Bossard teaches the exemplary formula where n’ = 4 species is roughly 9 mol% of the mixture (see Fig 4.1 and the table above, for calculation details see the 103 rejection of claim 1). This value is encompassed by “about 10 mol%” but not “about 7%” nor “about 5 mol%”. Bossard teaches the composition of PEGylated IL-2 variants with sufficient specificity to render obvious the instantly claimed ranges. See MPEP § 2144.05(I). Absent any evidence of criticality of these particular ratios, the composition is a matter of routine experimentation. See MPEP § 2144(III) and § 2144.05(II)(A).
*claim 12-15, 33, 35
Regarding claims 12-15, 33, and 35, Bossard teaches there are several amino acid residues for which the PEG could be attached, such as an N-terminal amine containing residues, such as lysine, within SEQ ID NO: 1-4 (pg 23, para 0117). Bossard teaches “Control of the desired number of polymers for any given moiety can be achieved by selecting the proper polymeric reagent, the ratio of polymeric reagent to the IL-2 moiety, temperature, pH conditions, and other aspects of the conjugation reaction” (pg 48, para 0153). In the absence of evidence of criticality, compositions comprising different ratios of n’ = 2 and n’ = 3 PEG moieties per IL-2 is a matter of user preference, and within the abilities of a person of skill in the art to generate. See the rejection of claims 9-11 which tabulates various exemplary formulas of Bossard.
claim 16-21
Regarding claims 16-21, Bossard teaches instant variable n is 2-4000 (pg 32, para 0127). In the absence of criticality for the PEG length, the range of Bossard renders obvious the ranges of n = 5-2000, 10-1000, 10-750, 10-500, 20-250, and 226.
claim 22-25
Regarding claims 22-25, Bossard teaches the PEG moiety is optionally about 300 Da, 1000 Da, 5000 Da, 10000 Da, 20000, or 55000 Da (pg 17, para 0096). In the absence of criticality for the PEG length, the range of Bossard renders obvious the ranges of 250-90000 Da, 1000-60000, 5000-60000, and 10000-55000.
*claim 26-31
Regarding claim 26-31, Bossard teaches there are several amino acid residues for which the PEG could be attached, such as an N-terminal amine containing residues, such as lysine, within SEQ ID NO: 1-4 (pg 23, para 0117). Bossard teaches “Control of the desired number of polymers for any given moiety can be achieved by selecting the proper polymeric reagent, the ratio of polymeric reagent to the IL-2 moiety, temperature, pH conditions, and other aspects of the conjugation reaction” (pg 48, para 0153). In the absence of evidence of criticality, compositions comprising different ratios of n’ = 1 (mono-PEG), n’ = 2 (di-PEG), n’ = 3 PEG (tri-PEG), and n’ > 3 (higher PEG) moieties per IL-2 is a matter of user preference and within the abilities of a person of skill in the art to generate. See the rejection of claims 9-11 which tabulates various exemplary formulas of Bossard.
claim 32, 34
Regarding claims 32 and 34, Bossard teaches there are several amino acid residues for which the PEG could be attached, such as an N-terminal amine containing residues, such as lysine, within SEQ ID NO: 1-4 (pg 23, para 0117). Bossard teaches the IL-2 variant of SEQ ID NO: 3 features a lysine at position 7 (bold, underlined), as suitable for polymer attachment. Note, the first lysine residue of Aldesleukin (Bossard SEQ ID NO: 1) occurs at position 28 (see 112(b) rejection of these claims).
Bossard_1 MYRMQLLSCIALSLALVTNSAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRML 60
Bossard_2 --------------------APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRML 40
Bossard_3 ---------------------PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRML 39
Bossard_4 --------------------APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRML 40
Aldesleukin MYRMQLLSCIALSLALVTNSAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRML 60
***************************************
Bossard_1 TFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSE 120
Bossard_2 TFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSE 100
Bossard_3 TFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSE 99
Bossard_4 TFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISRINVIVLELKGSE 100
Aldesleukin TFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSE 120
***********************************************.************
Bossard_1 TTFMCEYADETATIVEFLNRWITFCQSIISTLT 153
Bossard_2 TTFMCEYADETATIVEFLNRWITFCQSIISTLT 133
Bossard_3 TTFMCEYADETATIVEFLNRWITFSQSIISTLT 132
Bossard_4 TTFMCEYADETATIVEFLNRWITFCQSIISTLT 133
Aldesleukin TTFMCEYADETATIVEFLNRWITFCQSIISTLT 153
************************.********
Bossard teaches “Control of the desired number of polymers for any given moiety can be achieved by selecting the proper polymeric reagent, the ratio of polymeric reagent to the IL-2 moiety, temperature, pH conditions, and other aspects of the conjugation reaction” (pg 48, para 0153). In the absence of evidence of criticality, compositions comprising different ratios of n’ = 1 (mono-PEG), n’ = 2 (di-PEG), and n’ = 3 PEG (tri-PEG) moieties per IL-2 is a matter of user preference and within the abilities of a person of skill in the art to generate. Bossard teaches the PEG is about 20000 Da (pg 17, para 0096). See the rejection of claims 9-11 which tabulates various exemplary formulas of Bossard.
claim 36
Regarding claim 36, Bossard teaches the composition can comprise a pharmaceutically acceptable excipient (claim 16).
claim 37
Regarding claim 37, Bossard teaches the composition is intended for parenteral injection (pg 52, para 0175).
claim 38
Regarding claim 38, Bossard teaches the composition is suitable for subcutaneous administration (pg 52, para 0174).
claim 39
Regarding claim 39, Bossard teaches the composition can comprise a diluent, such as sterile water (pg 51, para 0173).
claim 40
Regarding claim 40, Bossard teaches the composition can have a pH of 5.0 (pg 56, para 0196).
claim 41
Regarding claim 41, Bossard teaches the composition can comprise sodium acetate (pg 50, para 0167), sodium chloride (pg 50, para 0163), and sucrose (pg 49, para 0162).
Claim 42
Regarding claim 42, Bossard teaches the composition can comprise 20 mM acetate at pH 5 (para 56, para 0196).
Bossard does not teach the composition having 10 mM sodium acetate, 110 mM sodium chloride, or 2% w/v of sucrose.
Dai teaches a method of developing a stable formulation for a protein conjugate (abstract; pg 1, para 0003), such as IL-2 (pg 7, para 0043). Dai teaches the composition can comprise about 2% w/v of sucrose, which is advantageous for increasing the solubility of the conjugate (pg 3, para 0021). Dai teaches a composition comprising 150 mM sodium chloride (pg 15, para 0117). Dai teaches the composition can comprise 50 mM sodium acetate (pg 16, para 0131), as part of a suitable buffering agent (pg 3, para 0021). Dai teaches the pH is optionally 5 (pg 4, para 0024).
It would have been obvious to combine the teachings of Bossard and Dai because (1) Bossard teaches the IL-2 PEG conjugate is compatible with acetate at pH 5.0; and (2) Dai teaches other conjugates of IL-2 can be formulated with similar amounts of sucrose, sodium acetate, and sodium chloride at pH 5.0. One of skill in the art would have had a reasonable expectation of success because Dai teaches the same quantity of sucrose, and similar quantities of sodium acetate and sodium chloride at the same pH using an IL-2 containing conjugate. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In the instant case, applicant has not provided any evidence of criticality, thus arriving at a formulation comprising the conjugate, 10 mM sodium acetate, 110 mM sodium chloride, or 2% w/v of sucrose is considered a matter of routine experimentation. See MPEP § 2144.05(II)(A).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
US9861705
Claims 1-5 and 9-42 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 9861705 (referred to herein as “the reference”) in view of Bossard et al. (WO2012065086) and Dai et al. (US20110166319).
Regarding instant claim 1, the reference claims an IL-2 conjugate comprising n’ = 1-7 water-soluble moieties (claim 1) wherein the water soluble moiety is a branched PEG (claim 2-3, 6, 8, 9).
Regarding instant claim, the reference claims the PEG moiety is 20000 Da (claim 4).
Regarding instant claims 3-5, and 7-10, the reference claims n’ = 1-3 (claim 10-13, 15).
Regarding instant claims 9-11, the reference claims n’ ≥ 4 (claim 16).
Regarding instant claim 36, the reference claims the composition contains a pharmaceutically acceptable excipient (claim 17).
The remaining claims 2, 12-35, 37-42; the ratios described within instant claims 3-35; and the chemical structures described in 1, 3-5, and 12-14; are obvious in combination over the references of Bossard and Dai as detailed in the 102 and 103 rejections above. It would have been obvious to combine the teachings of the reference and Bossard and Dai because (1) both Bossard and the reference are drawn to compositions comprising conjugates of IL-2 and PEG; and (2) Dai provides ingredients and quantities of those ingredients known to be compatible in stable formulations of IL-2 conjugates at pH 5.0. US9861705 claims priority to Bossard et al. (WO2012065086), thus is drawn to the same chemical structure.
Response to Arguments
Applicant's arguments filed 12/24/2025 have been fully considered but they are not persuasive.
103; pg 14, para 2
Applicant argues the “the claimed compositions solve important problems existing for prior therapies for the treatment of autoimmune and inflammatory conditions and provide an unforeseen technical advantage … the instant composition preferentially stimulates Tregs over Tcons.”
This argument would only overcome an obviousness rejection if the claims were drawn to a method of “preferentially stimulating Tregs over Tcons” as described by withdrawn claim 43. However, the instant claims examined herein are drawn solely to the compositions, wherein there is no requirement for the compositions to exhibit this property. Furthermore, MPEP § 2112.01(II) states “A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present,” thus in the instant case their property of selective Treg stimulation is inherent to their structure. Surprising results must be commensurate in scope with the instant claims, however, the instant claims are far broader, encompassing any use, thus there is no requirement that they preferentially stimulate Tregs.
103; pg 16, para 1
Applicant argues the cited references do not teach the particular ratios of IL-2 conjugates with differing quantities of mono-PEG, di-PEG, tri-PEG, and (≥4)-PEG. Applicant argues that the exemplary composition of Bossard fails to resolve the 1-mer from the 2-mer.
The instantly claimed ratios of PEGlyated IL-2 mixtures are substantially diverse, encompassing large differences chemical constituents and quantities of those constituents (e.g. encompassing a mixture of 50% di- and 50% tri-PEG; and a mixture of 28% di, 24% tri, 48% dodeca-PEG).
n’
Instant claim 1, 3
“about” instant claim 1, 3*
Instant RUR20kD-IL-2**
Bossard***
Mono-PEG
0-5
0 - 5.25
3.0
0 - 28
Di-PEG
28-60
26.6 - 63
42.4
0 - 28
Tri-PEG
24-65
22.8 - 68.25
46.6
28
Tetra-PEG
0-20
0 - 21
7.5
29
Penta-PEG
0-20
0 - 21
0.28 -0.72
10
≥6 PEG
0-20
0 - 21
0-0.22
5
*applicant defined “about” as equivalent to ±5%, which has been calculated into these ranges.
**values taken from instant Table 3. Standard deviation for 1-5 PEG’s was less than 4% thus these ranges were omitted, whereas that for 6-PEG was substantially higher (e.g. 44%), thus was calculated in the table above.
***The sum of mono + di cannot exceed 28.
Thus there is no requirement for Bossard to resolve the 1-mer from the 2-mer, because the instantly claimed composition encompasses mixtures comprising the same instantly claimed range of 1-mer species, as shown in the table above. This argument is further undermined in light of this being an exemplary mixture of Bossard, and not a claimed limitation of the invention. Bossard teaches “Control of the desired number of polymers for any given moiety can be achieved by selecting the proper polymeric reagent, the ratio of polymeric reagent to the IL-2 moiety, temperature, pH conditions, and other aspects of the conjugation reaction” (pg 48, para 0153). Thus, in the absence of evidence of criticality, compositions comprising different ratios of n’ = 2 and n’ = 3 PEG moieties per IL-2 is a matter of user preference, and within the abilities of a person of skill in the art to generate.
103; pg 18, para 4
Applicant argues their mixtures “possess important and differentiated technical effects which clearly distinguish these compositions from those of Bossard.” Applicant argues their compositions “were shown to mitigate or modulate particular immune responses in a manner unsuggested by Bossard”. Applicant repeats the argument regarding the preferential stimulation of Tregs. Applicant points to Example 10, Fig 17A-B as evidence of preferential Treg stimulation.
Firstly, the claimed compositions overlap substantially with those of Bossard, thus cannot possess alternative properties that are also not inherent to the compositions of Bossard. MPEP § 2112.01(II) states “A chemical composition and its properties are inseparable.” Secondly, Applicant has failed to provide any evidence of criticality showing the particular mixtures of PEGylated IL-2’s yield the purported Treg stimulation preference. For example, this could be demonstrated by provided experimental evidence showing that varying the relative mol% of di-PEG IL-2 has an effect on Treg stimulation over Tcon’s. Unfortunately, Example 10 uses a fixed composition (called “RUR20kD-IL-2”), thus fails to test whether the relative quantities of component within the mixture exhibit any effect. This composition has been described in instant Table 3 below. Importantly, this is the only exemplary mixture Applicant has described in the entire specification.
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276
836
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Example 10 merely shows that the one composition exhibits a dose-responsive effect (i.e. higher doses of the same composition are more effective than lower doses). Thirdly, because applicant is claiming the compositions and not a method of preferentially stimulating Tregs, there is no claimed requirement for the compositions to exhibit this property.
Double Patenting; pg 20, para 3
Applicant requests that the double patenting rejection over U.S. Patent No. 9861705 be deferred or held in abeyance. A request to hold a rejection in abeyance is not a proper response to a rejection. Rather, a request to hold a matter in abeyance may only be made in response to an OBJECTION or REQUIREMENTS AS TO FORM (see 37 CFR 1.111(b) and MPEP §714.02). Thus, the double patenting rejections of record have been maintained as no response to these rejections has been filled by applicant at this time.
Conclusion
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/L.A.E./
Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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