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 Claims
This reissue application was filed on 4/3/23 with amended independent claims 1 and 11. On 3/7/25, a preliminary amendment was filed further amending independent claims 1, 11, 14, and 16 and adding new claims 18-49.
Sequence Compliance
On 4/3/23, applicant submitted a request to transfer the computer-readable form (CRF) from parent application 17/245,679. As of 11/15/21, however, transfer requests of a CRF from a parent or related application to another application are no longer permitted. See 86 Fed. Reg. 57,035 (10/14/21); MPEP 2427, ¶ 24.17.
This application is governed by ST.26 rules. Sequence listings submitted in either non-provisional applications filed under 35 U.S.C. 111(a) or provisional applications filed under 111(b) that have a filing date on or after 7/1/22, including reissue applications, must be in XML format and comply with WIPO Standard ST.26 and 37 CFR 1.831 through 1.835. See MPEP 1410, 2415.01.
Summary of Requirements for Patent Applications
Filed On or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/patents-application-process/filing-online/legal-framework-efs-web), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.831-1.834 because it does not contain a “Sequence Listing XML” as a separate part of the disclosure. A “Sequence Listing XML” is required because sequences are disclosed throughout the application.
Required response - Applicant must provide:
• A “Sequence Listing XML” part of the disclosure, as described above in item 1. or 2.; together with
o A statement that indicates the basis for the amendment, with specific references to particular parts of the application as originally filed, as required by 37 CFR 1.835(a)(3);
o A statement that the “Sequence Listing XML” includes no new matter as required by 37 CFR 1.835(a)(4)
AND
• A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph as required by 37 CFR 1.835(a)(2), consisting of:
o A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
o A copy of the amended specification without markings (clean version); and
o A statement that the substitute specification contains no new matter.
Rejections—35 U.S.C. 251
Claims 1-49 are rejected under 35 U.S.C. 351 as being an impermissible recapture of broadened claimed subject matter surrendered in the application for the patent upon which the present reissue is based. See Greenliant Systems, Inc. et al v. Xicor LLC, 692 F.3d 1261, 103 USPQ2d 1951 (Fed. Cir. 2012); In re Shahram Mostafazadeh and Joseph O. Smith, 643 F.3d 1353, 98 USPQ2d 1639 (Fed. Cir. 2011); North American Container, Inc. v. Plastipak Packaging, Inc., 415 F.3d 1335, 75 USPQ2d 1545 (Fed. Cir. 2005); Pannu v. Storz Instruments Inc., 258 F.3d 1366, 59 USPQ2d 1597 (Fed. Cir. 2001); Hester Industries, Inc. v. Stein, Inc., 142 F.3d 1472, 46 USPQ2d 1641 (Fed. Cir. 1998); In re Clement, 131 F.3d 1464, 45 USPQ2d 1161 (Fed. Cir. 1997); Ball Corp. v. United States, 729 F.2d 1429, 1436, 221 USPQ 289, 295 (Fed. Cir. 1984).
The reissue application contains claims that are broader than the issued patent claims. The record of the application for the patent shows that the broadening aspect (in the reissue) relates to claimed subject matter that applicant previously surrendered during the prosecution of that application. Finally, the claims have not been otherwise materially narrowed to avoid the recapture rule.
According to the three-step analysis in MPEP 1412.02(II):
Step 1. The reissue application contains claims that are broader than the issued patent claims.
The reissue application both amends the issued independent claim and adds new independent claims. Claim 1 of underlying US Patent 11,597,753 reads:
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The patented claims are a fusion protein comprising, among other things, an IL-2Rβ binding region connected to a first cleavable linker. It also contains a double mutein of IL-2 with R81E and L85T mutations.
Amended claim 1 is drawn to the same fusion protein but allows that it may include either an IL-2Rα binding region or an IL-2Rβ binding region. Claim 1 also newly permits an IL-2 mutein comprising either R81E and L85T or an R81E and L85I mutation. Each of claims 1-17 are broader in scope than the issued claims because the claims no longer limit the moiety connected to the first cleavable linker to be an IL-2Rβ binding region, and they no longer limit the IL-2 to an R81E L85T mutein.
New claim 18 is independent and is broader than issued claim 1. It is drawn to the same sort of fusion protein but permits that the IL-2 portion may be IL-2 wild type or mutein (i.e., any mutein). It also allows that the IL-2R binding region may be either an IL-2Rα binding region or an IL-2Rβ binding region. It also eliminates the requirement for a particular binding affinity at two different pH levels. Each of claims 18-31 are broader in scope than the issued claims because the claims no longer limit the moiety connected to the first cleavable linker to be an IL-2Rβ binding region, they no longer limit the IL-2 to an R81E L85T mutein, and they no longer make any requirements about the binding affinity for IL-2R.
New claim 33 is independent and is broader than issued claim 1. It is similar to claim 18 except that it requires the presence of a target-binding peptide. Each of claims 33-49 are broader in scope than the issued claims because the claims no longer limit the moiety connected to the first cleavable linker to be an IL-2Rβ binding region, they no longer limit the IL-2 to an R81E L85T mutein, and they no longer make any requirements about the binding affinity for IL-2R.
Step 2. The broader aspects of the reissue claims relate to surrendered subject matter.
Original claim 1 presented in underlying application 17/245,679 on 4/30/21 was directed to:
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Relevant to this rejection, dependent claim 18 read:
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In the underlying ’679 application, the examiner imposed a restriction requirement and requirement for election of species on 7/27/22. Within that requirement, among other things, the examiner distinguished between patentably distinct species of IL-2 mutein (see pages 11-12) and between an IL-2Rα binding region and an IL-2Rβ binding region. (See pages 15-16.) The examiner also suggested that a fusion protein containing a target-binding peptide was patentably distinct from one lacking it. (Pages 15-16, identifying the fusion protein as “optionally [comprising] a target-binding polypeptide”.) The examiner wrote:
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(Pages 11 and 16.)
On 9/27/22, applicant replied to the restriction requirement and, among other things, elected “IL-2 SEQ ID NO:3” (which corresponds to IL-2 with an R81E L85I double mutation) and “IL-2Rα” (i.e., the IL-2-binding region of IL-2Rα). (Reply at 6.) Applicant did not indicate that the elected fusion protein contains the optional target-binding polypeptide. (Reply at 6.) Applicant indicated the election was made with traverse but provided no arguments as to the requirement for an election between the species.
On 10/31/22, before an Office action on the merits could be issued in the underlying application, applicant and the examiner held an interview. The summary of that interview makes reference to rejections under 35 U.S.C. 112(a) for lack of written description, 35 U.S.C. 112(b) for indefiniteness, 35 U.S.C. 102 for anticipation over Winston (US 2020/0040052), and 35 U.S.C. 103 for obviousness over Winston in view of Sun et al. (2019; Nature Communications 10:3874). Both references were made of record in the 11/10/21 information disclosure statement.1 The interview summary evidences that the examiner found the claims and elected subject matter were rejectable both over prior art and under 35 U.S.C. 112.
With the examiner’s authorization, applicant submitted a supplemental claim amendment on 11/1/22. (See remarks at 5.) The remarks expressly state that the amendments were made in response to the interview, which discussed proposed rejections, and they thank the examiner for her consideration of the amendments, indicating they were discussed at the interview. (Remarks at 5.) As such, the record also evidences that the 11/1/22 amendments were made in response to the examiner’s proposed rejections.
The 11/1/22 supplemental listing amended claim 1:
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Critically, the amendment shifted the binding region from the previously elected IL-2Rα to the other option, IL-2Rβ. It also narrowed the IL-2 portion from “wild type or mutein” to “an IL-2 mutein comprising an R81E and L85T mutation,” which corresponds to SEQ ID NO:4, shifting the elected IL-2 mutein as well. In permitting applicant to shift from the elected species in the 11/1/22 amendment, the examiner effectively withdrew the requirement for species election between IL-2Rα and IL-2Rβ and between elected SEQ ID NO:3 and allowed SEQ ID NO:4.2 Applicant declined to continue prosecuting IL-2Rα and SEQ ID NO:3 in the underlying application.
Limiting the moiety connected to the first cleavable linker to an IL-2Rβ binding region and limiting the IL-2 molecule to an IL-2 mutein comprising an R81E and L85T mutation are surrender-generating limitations, and they have been eliminated in the reissue claims because the claims are now open to additional options canceled in the underlying application in response to proposed rejections, namely the IL-2 binding region of IL-2Rα and an IL-2 mutein comprising an R81E and L85I mutation. Furthermore, claims 14 and 46 expressly recite SEQ ID NO: 3, which is surrendered subject matter.
Critically to claims 18 and 33, allowed claim 1 also specified the degree of binding affinity for IL-2Rβ at two pH levels. This amendment introduced a third surrender-generating limitation because it narrowed the scope of the activatable IL-2 fusion protein to only those with that particular function. This limitation has been removed from reissue independent claims 18 and 33.
Step 3. The reissue claims were not materially narrowed in other respects such that the recapture rule was avoided.
The surrendered subject matter of original claim 1 in the underlying ’679 application was the IL-2 fusion protein comprising, among other things, the IL-2 binding region of IL-2Rα as the moiety connected to the first cleavable linker and an IL-2 portion that is an IL-2 mutein comprising an R81E and L85I mutation. Activatable IL-2 fusion proteins that do not have the binding profile of the issued claims were likewise surrendered. The claims have not otherwise been narrowed in any way, so impermissible recapture has not been avoided.
Claim Objections
Claim 1 is objected to because it ends in two periods.
Warning—Duplicate Claims
Applicant is advised that should claim 17 be found allowable, claim 32 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).3
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 1-49 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.
A. Claim 1 is an activatable IL-2 fusion protein comprising (a) an IL-2 mutein comprising an R31E and L85T mutation, (b) a first cleavable linker connected to the IL-2 mutein, and (c) an IL-2Rα or IL-2Rβ binding region connected to the first cleavable linker. The claim then goes on to require (d) a half-life extender “connected to the IL-2 or the IL-2 receptor alpha or beta.” (Line 6.) This is confusing because it is unclear whether “the IL-2” refers to the IL-2 mutein of line 2 or to IL-2 per se (i.e., wild-type IL-2). Claims 18 and 33 have similar issues and are rejected for the same reason.
B. Claim 1 refers to “an interleukin-2 receptor alpha or beta binding region” at line 5. It is unclear whether this term refers to the portions of IL-2Rα or IL-2Rβ that bind to IL-2 or to a region of another moiety that binds IL-2Rα or IL-2Rβ. If the former is the case, modifying the claims to refer to “the IL-2-binding region of an IL-2 receptor alpha or beta” would be remedial. Claims 18 and 33 have similar issues and are rejected for the same reason.
C. Furthermore, it is unclear whether “the IL-2 receptor alpha or beta” at line 7 of claim 1 means that IL-2Rα and/or IL-2Rβ per se is part of the fusion protein or whether applicant intended to refer to the IL-2Rα or IL-2Rβ binding region of line 4. The antecedent basis for the limitations of element (d) as identified above are unclear. Claims 18 and 33 suffer similar deficiencies and are likewise rejected.
D. Claim 1 goes on to require that cleavage of the first cleavable linker “releases the IL-2 mutein from the IL2-R beta.” (Lines 8-9.) This is confusing because again, it is unclear whether IL-2 receptor beta is part of the complex or whether applicant intended to refer to the IL-2Rβ binding region of line 4. Even if the latter is the case, this limitation eliminates the option for the release from IL-2Rα, so it is unclear whether this limitation only applies to those embodiments in which the moiety in element (c) pertains to IL-2Rβ. In other words, it is unclear whether this limitation intends to limit the IL-2R to be the beta form. The limitation therefore lacks clear antecedent basis. See MPEP 2173.05(e) (“[I]f two different levers are recited earlier in the claim, the recitation of “said lever” in the same or subsequent claim would be unclear where it is uncertain which of the two levers was intended.”) Claims 18 and 33 suffer similar deficiencies and are likewise rejected.
E. Finally, claim 1 refers at line 9 to a retention of “binding to the IL-2R alpha or beta at pH 6.4.” It is unclear whether “the IL-2R alpha or beta” refers to the one at line 7, the one at lines 8-9, or the one at line 10. The antecedent basis for this limitation is therefore unclear. See MPEP 2173.05(e) (“two levers” example).
Claims 2-17, 19-32, and 34-49 depend variously from claims 1, 18, and 33 and do not rectify the indefiniteness, so they must also be rejected under 35 U.S.C. 112(b).
F. Claims 3-6 and 13 indicate that the first cleavable linker “is cleaved by” various proteases. It is unclear whether these claims intend to require that the linker has in fact been cleaved within the composition or whether they are identifying proteases capable of cleaving the linker. If the latter is the case, replacing “cleaved” with “cleavable” in each claim would be remedial. Claims 20-23, 30, 35-38, and 45 suffer similar deficiencies.
G. Claim 9 is indefinite because it lists an incomplete group of options, so it is unclear whether the entire Markush group is represented. The word “and” or “or” must appear between the last two items in each list. (See line 13 between “CD303” and “CD304”.) Claim 41 suffers a similar deficiency.
H. Claim 9 is further indefinite for reciting broader limitations within parentheses. Line 4 refers to “Fibroblast Activation Protein Alpha (FAP),” which is confusing because a fibroblast activation protein (FAP) beta also exists. It is unclear whether the material in parentheses opens the claim to other FAPs or not. The same applies to “EPH Receptor A4 (EphA)” at line 5 because several EphA proteins exist, not just EphA4. It is unclear whether the material in parentheses opens the claim to other ephrin receptors or not. Claim 41 suffers a similar deficiency.
I. Claim 10 is confusing because it appears to include an active step in which the aIL-2 of claim 2 reduces its own in vivo toxicity compared to IL-2. The claim recites a composition, not a method. Claim 42 suffers a similar deficiency.
J. Claim 11 refers to “IL-2 receptor alpha or beta” at lines 3, 5, 7, 8, 9, and 11, but it is unclear whether IL-2Rα or IL-2Rβ per se are part of the fusion protein or whether applicant intended to refer to the IL-2Rα or IL-2Rβ binding region of claim 1, line 4. Claims 28 and 43 suffer similar deficiencies.
K. Claim 11 refers to “the antibody Fe region” at lines 3-4, 5-6, 8, 10, and 12. Claim 2 does not refer to “an antibody Fe region.” There is therefore insufficient antecedent basis in claim 2 for this limitation of claim 11.4
L. Claim 16 refers to “the interleukin-2 receptor binding beta region” at line 2. There is no antecedent basis for this limitation in claim 1. Claim 16 also refers to “the half-life extender or an antibody Fe region” of claim 1, but claim 1 does not require an antibody Fe region. It is unclear whether claim 16 intends to introduce an antibody Fe region as a required element of the composition or whether it intends to refer to “the antibody Fc region of claim 2.”
M. Finally, claim 16 refers to “the aIL-2 of claim 1, wherein . . . an optional target-binding protein, is a human sequence.” Claim 1 does not refer to an optional target-binding protein, so this limitation’s antecedent basis is unclear. Claim 48 suffers a similar deficiency.
N. Claim 28 depends from claim 18 and refers to “the second linker” at lines 7 and 9 and to “the second cleavable linker” at lines 15 and 17. There is no antecedent basis for these limitations. Claim 18 only recites a first cleavable linker. Claim 43 suffers similar deficiencies at lines 7, 9, 15, and 17 with respect to claim 33.
O. Claim 28 depends from claim 18 and refers repeatedly to “the antibody Fc region.” Claim 18 does not recite an antibody Fc region. Claim 28 therefore lacks antecedent basis in claim 18. Claim 43 suffers similar deficiencies with respect to claim 33 and therefore lacks antecedent basis there.
P. Claim 48 refers to “an antibody Fc region” at line 3, but claim 33 does not recite an antibody Fc region. Claim 48 therefore lacks antecedent basis in claim 33.
Claim Interpretation
Independent claims 1, 18, and 33 are indefinite for the reasons set forth above but have been interpreted as follows for the remainder of the Office action:
1. An activatable interleukin-2 (aIL-2) fusion protein comprising:
an interleukin-2 (IL-2) mutein comprising an R81E and L85T mutation or comprising an R81E and L85I mutation;
a first cleavable linker connected to the IL-2 mutein;
connected to the first cleavable linker, the IL-2-binding region of IL-2Rα or IL-2Rβ; and
a half-life extender connected to the IL-2 mutein, the IL-2-binding region of IL-2Rα, or the IL-2-binding region of IL-2Rβ,
wherein cleavage of the first cleavable linker releases the IL-2 mutein from the IL-2-binding region of IL-2Rα or the IL-2-binding region of IL-2Rβ, and
wherein the IL-2 mutein has increased binding affinity for IL-2Rα or IL-2Rβ at pH 7.4 and retains binding to IL-2Rα or IL-2Rβ at pH 6.4.
18. An activatable interleukin-2 (aIL-2) fusion protein comprising:
a wild-type interleukin-2 (IL-2) or IL-2 mutein;
a first cleavable linker connected to the wild-type interleukin-2 (IL-2) or IL-2 mutein;
connected to the first cleavable linker, the IL-2-binding region of IL-2Rα or IL-2Rβ; and
a half-life extender connected to the IL-2 mutein, the IL-2-binding region of IL-2Rα, or the IL-2-binding region of IL-2Rβ,
wherein cleavage of the first cleavable linker releases the IL-2 mutein from the IL-2-binding region of IL-2Rα or the IL-2-binding region of IL-2Rβ.
33. An activatable interleukin-2 (aIL-2) fusion protein comprising:
a wild-type interleukin-2 (IL-2) or IL-2 mutein;
a first cleavable linker connected to the wild-type interleukin-2 (IL-2) or IL-2 mutein;
connected to the first cleavable linker, the IL-2-binding region of IL-2Rα or IL-2Rβ;
a target-binding polypeptide; and
a half-life extender connected to the IL-2 mutein, the IL-2-binding region of IL-2Rα, or the IL-2-binding region of IL-2Rβ,
wherein cleavage of the first cleavable linker releases the IL-2 mutein from the IL-2-binding region of IL-2Rα or the IL-2-binding region of IL-2Rβ.
Consistent with the specification and SEQ ID NO: 20, the term “IL-2Rα binding region” is interpreted for 35 U.S.C. 112(a) as referring to a region of IL-2Rα that binds to IL-2. (See Figure 1 and SEQ ID NO:20, which is residues 3-214 of wild-type human IL-2Rα and was previously presented in the underlying application’s claim 18 as a species of “IL-2Rα.”) Similarly, the term “IL-2Rβ binding region” is interpreted as referring to a region of IL-2Rβ that binds to IL-2. (See SEQ ID NO:21, which is residues 1-214 of human IL-2Rβ.)
The IL-2 mutein’s binding affinity describes how that portion of the fusion protein binds IL-2Rα or IL-2Rβ outside the fusion protein, not how it binds the IL-2Rα binding region or IL-2Rβ binding region found within the fusion protein. This reading is consistent with the specification, which refers to the IL-2 mutein’s binding of IL-2Rβ in solution at pH 6.4 as assayed by ELISA. (Column 10, lines 22-31.)
Claim Rejections - 35 USC § 112(a)
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 1-17 and 27 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.
As discussed above, claim 1 is interpreted as being drawn to an aIL-2 fusion protein comprising (a) an IL-2 mutein with R81E and L85T mutations or one with R81E and L85I mutations, connected to (b) a first cleavable linker, connected to (c) a portion of IL-2Rα or IL-2Rβ that binds IL-2. The fusion protein further comprises (d) a half-life extender connected to either element (a) or element (c). When the fusion protein is cleaved at the linker, the IL-2 mutein is released from that portion of IL-2Rα or IL-2Rβ that binds it. Most critically to this rejection, the IL-2 mutein has increased binding affinity for IL-2Rα or IL-2Rβ at pH 7.4 and retains the binding at pH 6.4. This final limitation raises issues under 35 U.S.C. 112(a). The application as filed does not provide support for fusion proteins containing IL-2 muteins with these required binding properties, particularly with respect to IL-2[Symbol font/0x61].
MPEP 2163 instructs that to satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. An applicant shows that the inventor was in possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that inventor was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Specifically, applicant has not shown possession of an IL-2 mutein that binds IL-2Rα or IL-2Rβ with increased affinity at pH 7.4 but that retains the binding at pH 6.4.
Around the claims’ effective filing date, skilled artisans understood that IL-2Rα and IL-2Rβ bind IL-2 in different ways. Winston (US 2020/0040052; cited above and as US PGPub reference 3 on 4/3/23 IDS) discusses the manner in which the IL-2 receptor binds its ligand. Winston discloses that IL-2Rα contains “a large hydrophobic binding surface surrounded by a polar periphery that results in a relatively weak interaction (Kd 10-8 M) with rapid on-off binding kinetics.” (Paragraph 79.) By contrast, IL-2Rβ associates with IL-2 “through a distinct polar interaction.” (Paragraph 79.) Winston also teaches that in the cell, IL-2Rβ only binds IL-2 once IL-2 has already bound to IL-2Rα. (Paragraph 79.) The person of ordinary skill in the art would therefore have understood that a given IL-2 mutein with mutations at particular sites that strongly bind IL-2Rβ would not necessarily bind IL-2Rα with the same affinity.
This finding is supported by the teachings of Sun et al. (2019; Nature Communications 10:3874; cited above and as NPL reference 2 on 4/3/23 IDS). Sun describes IL-2 muteins that have increased CD122 (IL-2Rβ) binding and decreased CD25 (IL-2Rα) binding. (Abstract.) Sun also teaches IL-2 muteins that prefer IL-2Rα. (Page 2, column 1.) The person of ordinary skill in the art would therefore have understood that an IL-2 mutein that binds IL-2Rβ with given binding properties would not necessarily bind IL-2Rα with the same properties.
As for the embodiment in which the IL-2 mutein is connected to a half-life extender, the person of ordinary skill in the art would also have understood that receptor binding is affected by the presence of these moieties. Charych (2016, Clinical Cancer Research 22:680-690; 4/3/23 IDS NPL reference 1) discloses a conjugate of IL-2 connected to six releasable polyethylene glycol (PEG) molecules. (Abstract; page 682, column 2.) Charych teaches that these PEG molecules are attached at key sites on IL-2 for IL-2Rα receptor binding. (Page 682, column 2.) Charych teaches that the PEGylated IL-2 is slowly released upon administration as the PEG chains are cleaved off, thereby preventing immediate IL-2/IL-2Rα receptor binding. (Page 683, column 1.) The skilled artisan would therefore have understood that connecting a half-life extender to the IL-2 mutein within the claimed fusion protein would alter its binding to its receptor.
Chen et al. (WO 2021/030633, filed 8/13/19; reference N) does teach that IL-2 mutations including R81E and L85T were known to modify IL-2 binding to its receptors. (Page 3, lines 5-10.) Chen does not, however, teach that the effects of these two particular mutations on both IL-2Rα and IL-2Rβ binding were known or predictable. Chen also does not address the embodiment of claim 1 in which the mutations are R81E and L85I.
Oh et al. (US Patent 11,746,137, filed 3/31/20; reference A) likewise teaches an IL-2 mutein with substitutions including R81E and L85T to increase IL-2Rβ binding affinity. (Column 43, analog 63.) Oh does not, however, indicate that analog 63 binds IL-2Rβ at the claimed pH levels or binds IL-2Rα at all. (See Table 3 at columns 64-66, testing the binding affinity of some analogs, but not analog 63, at an undisclosed pH.) Oh also does not address the embodiment of claim 1 in which the mutations are R81E and L85I.
Bernett et al. (US 2019/0241638; reference B) assayed the IL-2Rα binding affinity of numerous IL-2 muteins at pH 7.4, but none of them have R81E and L85T or R81E and L85I mutations. (Figures 11A-11C; paragraph 32.) Bernett found R38, T41, and F42, as well as Q126, to be the residues that attenuate pH-dependent IL-2Rα binding. (Paragraphs 29, 254-263; Figure 8B.) Bernett also did not assay any muteins at pH 6.4, but rather at pH 6.0. (Paragraph 259, e.g.) Bernett also does not address the embodiment of claim 1 in which the mutations are R81E and L85I.
Ast et al. (US 2012/0244112; reference C) found residues F42, Y45, and L72 as critical for modifying IL-2Rα binding affinity at pH 7.4 but does not test IL-2 with R81E and L85T substitutions or R85E and L81I substitutions or either one’s binding affinity at pH 6.4. (Paragraphs 14 and 174.)
Rao et al. (2005, Biochemistry 44: 10696-10701; reference U) generated IL-2 mutants with increased IL-2Rα binding affinity at pH 7.4, but none were IL-2 with R81E and L85T substitutions or R81E and L85I substitutions, and Rao did not test at pH 6.4. (Table 1; page 10698.)
The teachings of the prior art do not provide a correlation between a given IL-2 mutein’s structure and its binding affinity for its receptors at the claimed pH levels. The as-filed disclosure does not teach such a correlation either because the experimental data does not disclose one.
Applicant describes several IL-2 muteins, all of which “reduce the binding to IL2R alpha with altered binding to receptor beta.” (Underlying ’753 patent at column 8, lines 49-51.) Specifically, the disclosed IL-2 muteins contain an F42A substitution to eliminate IL-2Rα binding in addition to other mutations that increase IL-2Rβ binding. (Column 8, line 65, through column 9, line 1; column 10, line 31.) Applicant teaches that SEQ ID NOs: 3 and 4, but not IL-2 F42A, bind IL-2Rβ at pH 6.4. (Column 10, lines 28-31.) SEQ ID NO:3 is IL-2 with F42A, R81E, and L85I substitutions, while SEQ ID NO:4 is IL-2 with F42A, R81E, and L85T substitutions. (See column 11, lines 26-35.) As such, SEQ ID NO:4 represents the only IL-2 mutein within the scope of claim 1 that the ’753 patent tested for binding to IL-2Rβ at pH 6.4.
Claim 1 further requires increased receptor-binding affinity at pH 7.4 relative to some unstated standard. The ’753 patent actually contains no assays at pH 7.4; the working example’s near-neutral pH was pH 6.9. (Column 10, lines 26-28.) It is therefore not clear that the person of ordinary skill in the art would have concluded that applicant possessed any IL-2 mutein with “increased binding affinity for IL-2R alpha or beta at pH 7.4” relative to any standard.
The working examples also do not investigate any IL-2 muteins’ receptor binding affinity when they are connected to a half-life extender.
Given the teachings of the cited prior art about the unpredictability of IL-2’s binding to its alpha and beta receptor subunits, the showing in the specification is insufficient to demonstrate possession of the invention as applicant claims it.
It is not sufficient that skilled artisans were aware that mutating the claimed two positions in IL-2 could somehow change its receptor-binding profiles. The written-description requirement is not met simply because the person of skill would have known how to make the claimed IL-2 mutein and test it for IL-2R binding. Enablement and written description are separate requirements of 35 U.S.C. 112(a). See MPEP 2161; MPEP 2163(I) (“conclusive evidence of a claim’s enablement is not equally conclusive of that claim’s satisfactory written description”) (quoting In re Curtis, 354 F.3d 1347, 1357, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004)).
“For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus.” MPEP 2163(II)(A)(3)(a)(ii). Here, the art recognized that IL-2Rα and IL-2Rβ bind IL-2 by two different mechanisms and according to two different kinetic profiles. The art also recognized how to make IL-2 muteins with substitutions at key residues to affect IL-2R binding, but there was no known correlation between a given substitution pattern and its effect on IL-2’s ability to bind its alpha or beta receptor subunit. Applicant discloses one R81E L85T mutein of IL-2 (SEQ ID NO:4) and one R81E L85I mutein of IL-2 (SEQ ID NO:3) and shows they bind IL-2Rβ at pH 6.4, but there is no data provided at pH 7.4 or data on IL-2Rα binding at all. There is also no data addressing the binding affinity of any IL-2 muteins connected to a half-life extender. Because of the unpredictable relationship between IL-2 mutations and their effect on receptor binding, the person of ordinary skill in the art would not have considered applicant’s data on SEQ ID NOs: 3 and 4 as demonstrating possession of the entire invention as claim 1 recites it.
Claims 2-17 depend from claim 1 and do not rectify the issue of the fusion protein’s claimed binding affinity, so they are also rejected under 35 U.S.C. 112(a) for inadequate written description. Claim 27 is included because it too contains the binding profile that is unsupported by the as-filed disclosure.
Claim Rejections - 35 USC § 251
Original Patent
The following is a quotation of the first paragraph of 35 U.S.C. 251:
(a) IN GENERAL.—Whenever any patent is, through error, deemed wholly or partly inoperative or invalid, by reason of a defective specification or drawing, or by reason of the patentee claiming more or less than he had a right to claim in the patent, the Director shall, on the surrender of such patent and the payment of the fee required by law, reissue the patent for the invention disclosed in the original patent, and in accordance with a new and amended application, for the unexpired part of the term of the original patent. No new matter shall be introduced into the application for reissue.
MPEP 1412.01 states that the reissue claims must be for the same invention as that disclosed as being the invention of the original patent. MPEP 1412.01 further provides guidelines for determining whether the reissue claims are “for the invention disclosed in the original patent” as:
(A) the claims presented in the reissue application are described in the original patent specification and enabled by the original patent specification such that 35 U.S.C. 112, first paragraph is satisfied; and
(B) nothing in the original patent specification indicates an intent not to claim the subject matter of the claims presented in the reissue application.
The presence of some disclosure (description and enablement) in the original patent should evidence that applicant intended to claim or that applicant considered the material now claimed to be his or her invention.
Further, the Federal Circuit addressed the “original patent” requirement of 35 USC 251 in Antares Pharma, Inc. v. Medac Pharma Inc. and Medac GmbH, 771 F.3d 1354, 112 USPQ2d 1865 (Fed. Cir. 2014). In Antares, the reissue claims covered embodiments of injection devices (not restricted to jet-injection devices) which the Applicant admitted was a different invention from what was originally claimed. Id. at 1356. The Federal Circuit adopted the Supreme Court's explanation of the “same invention” requirement as “if the original patent specification fully describes the claimed inventions, but not if the broader claims ‘are [] merely suggested or indicated in the original specification.’” Id. at 1359. The Federal Circuit further stated that although wording in 35 USC 251 was changed from “same invention” to “original patent” no change in substance was intended. Id. at 1360.
Based on Antares, a review of the specification is necessary to determine whether the original specification adequately discloses the invention of the reissue claims. Like in Antares, the original specification in this case fails to disclose the invention claimed. For the reasons discussed above, the claims presented in the reissue application are not described in the original patent specification such that 35 U.S.C. 112(a) is satisfied. Therefore, claims 1-17 and 27, which are directed to aIL-2 fusion proteins having a particular IL-2R binding profile, do not satisfy the “original patent” requirement.
Claims 1-17 and 27 are accordingly rejected under 35 U.S.C. 251 for not claiming subject matter directed to the invention disclosed in the original patent.
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.
Claims 18-24, 28-30, 33-39, 41-45, 48, and 49 are rejected under 35 U.S.C. 103 as being unpatentable over Winston et al. (US 20200040052; PGPub reference 3 on 4/3/23 IDS). Winston is prior art under 35 U.S.C. 102(a)(1) because it was published before 4/30/20, and it is also prior art under 35 U.S.C. 102(a)(2) because it was effectively filed before that date.
Winston teaches activatable fusion proteins comprising a cytokine polypeptide or mutein thereof attached by a cleavable linker to a “blocking moiety” that blocks or inhibits the receptor activating function of the cytokine, plus a half-life extender connected to the blocking moiety such that cleavage of the linker releases the cytokine from the blocking moiety. (Figure 2; paragraphs 90 and 93; claim 1.) Winston teaches that the linker is cleavable by proteases present at a desired target site (e.g., a tumor) and that upon protease action, IL-2 is freed from the fusion protein such that it can bind IL-2R at the target site and exert a therapeutic effect. (Figure 2; paragraphs 7, 14, 29-34.) Regarding claim 33 and its dependents, Winston teaches that the activatable fusion protein may also comprise a targeting domain. (Figure 3; claim 2.)
Winston teaches that wild-type IL-2, a cytokine, binds IL-2R[Symbol font/0x61]. (Paragraphs 77, 79, and 90.) Winston teaches engineering IL-2 muteins that bind the IL-2R complex generally or the IL-2R[Symbol font/0x61] subunit specifically with an affinity that differs from that of the corresponding wild-type IL-2. (Paragraphs 235-236.) Winston teaches that the blocking moiety in the activatable fusion protein may be IL-2R[Symbol font/0x61] or IL-2R[Symbol font/0x62] or a fragment thereof that inhibits the ability of IL-2 to bind and/or activate its receptor in cells by sterically blocking and/or by noncovalently binding to IL-2. (Paragraphs 111 and 113.)
It would have been obvious before the effective filing date to make an activatable IL-2 fusion protein comprising an IL-2 wild type or mutein connected by a cleavable linker to a region of IL-2R[Symbol font/0x61] or IL-2R[Symbol font/0x62] that binds IL-2, connected to a half-life extender, such that cleavage of the linker releases the IL-2 wild type or mutein from the IL-2-binding region of IL-2R[Symbol font/0x61] or IL-2R[Symbol font/0x62]. This is so because Winston teaches that the IL-2-binding portion of IL-2R[Symbol font/0x61] and IL-2R[Symbol font/0x62] are available as “blocking moieties” in an activatable fusion protein comprising IL-2, plus Winston expressly suggests adding a half-life extender to improve stability of the protein upon administration. It would have been obvious to connect the IL-2 (wild-type or mutein) to the IL-2-binding portion of IL-2R[Symbol font/0x61] or IL-2R[Symbol font/0x62] via a cleavable linker because Winston teaches doing so and discloses that proteases at the desired delivery site are able to cleave the linker and free therapeutic IL-2 to permit it to bind IL-2R at that site.
Regarding claims 19, 28, 34, and 43, Winston teaches that including an antibody Fc region increases serum half-life. (Paragraphs 111 and 158.) It would therefore have been obvious to select an antibody Fc region as the half-life extender in Winston’s activatable fusion protein.
Regarding claims 28 and 43, Winston depicts numerous physical configurations of the components of the fusion protein (Figures 2, 3, 4a, and 4b), and Winston contemplates different positions of these components. (Paragraphs 198 and 298.) Selecting any order of the components within the fusion protein would therefore have been routine optimization within the parameters set forth by Winston. See MPEP 2144.05(II).
Regarding claims 20-23, 29, 35-38, and 44, Winston teaches that MMPs including MMP14 and caspases including caspase-3 are known to be associated with diseased cells or tissues. (Paragraphs 182-183.) Winston teaches that cleavage sites for these proteases were known. (Paragraph 184.) It would have been obvious to select a cleavable linker cleaved by one of these proteases in order to release therapeutic IL-2 at a disease site.
Regarding claims 24 and 39, Winston teaches including multiple copies of the cytokine to facilitate dimerization. (Paragraph 198.) Winston depicts a homodimer. (Figure 1d.) It would have been obvious to configure an activatable IL-2 fusion protein as a homodimer according to Winston’s express guidance.
Regarding claims 30 and 45, Winston teaches that the linker may be cleaved by, for example, granzyme B (an apoptotic enzyme), kallikreins (inflammation-associated enzymes), elastase (an inflammation mediator), cathepsin G (an apoptosis promoter and inflammation regulator), PR-3 (an apoptosis promoter and inflammation regulator), or calpains (inflammation regulators). Winston further teaches that cleavage sites for these proteases were known. (Paragraph 183, Tables 1 and 1a.) It would therefore have been obvious to select a linker cleavable by one of these enzymes in order to release therapeutic IL-2 at a site of apoptosis or inflammation.
Regarding claim 41, Winston teaches that the target antigen may be, among other things, HER2, HER3, CEA, cMet, or EpCAM. (Paragraphs 20 and 21.) It would therefore have been obvious to select one of these as the target of the target-binding polypeptide for Winston’s construct.
Regarding claim 42, Winston teaches that the linker is designed to be cleaved at the site of desired cytokine activity, for example in the tumor microenvironment, avoiding off-target cytokine activity and reducing overall toxicity of cytokine therapy. (Paragraph 7.) The skilled artisan would therefore have reasonably expected that the activatable IL-2 fusion protein reduces in vivo toxicity associated with IL-2 therapy, and it would have been obvious to generate that fusion protein for that reason.
Regarding claim 48, Winston teaches using human IL-2 in the fusion protein. (Paragraphs 8 and 9.) Winston also teaches using human serum albumin or a human Fc antibody fragment as the half-life extender. (Paragraph 158.) Selecting a human protein would therefore have been obvious.
Regarding claim 49, Winston teaches providing the activatable fusion protein together with a physiologically acceptable carrier and/or excipient. (Paragraph 24.) It would therefore have been obvious to formulate the activatable fusion protein of claim 33 with a carrier according to Winston’s express suggestion.
Claims 25, 31, 40, and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Winston et al. (US 20200040052) in view of Sun et al. (2019; Nature Communications 10:3874; cited above and as NPL reference 2 on 4/3/23 IDS). Sun is prior art under 35 U.S.C. 102(a)(1) because it was published before 4/30/20.
The teachings of Winston are relied upon as above. Specifically, Winston discloses numerous embodiments of fusion proteins that can be dimerized and teaches that two copies of a cytokine facilitate dimerization. (Paragraph 198; Figures 1-3.) Winston also teaches many options for the blocking moiety (paragraphs 111-113) and for the half-life extender (paragraphs 111 and 158-164). Winston’s constructs are useful for treating cancer by releasing IL-2 to the tumor microenvironment (TME). (Paragraphs 4 and 6.) Winston’s activatable IL-2 fusion protein reduces the toxicity of IL-2. (Paragraphs 7, 57, 76, and 89.) Winston teaches that the construct may bind EGFR. (Paragraph 172, e.g.)
Regarding claims 25 and 40, Winston does not teach a heterodimer. Regarding claims 31 and 47, Winston does not specify reduced toxicity in any particular organ.
Sun discloses making a heterodimer with its super mutant IL-2/antibody complex (Ab-sumIL2). (Abstract; page 4, column 1.) Specifically, Sun teaches an activatable IL-2 fusion protein (“super mutant IL-2,” sumIL-2) with a sumIL-2-Fc monomer in one arm and anti-human EGFR in another arm. (Page 4, column 1.) Sun’s fusion protein provides efficient delivery of sumIL-2 not only to target EGFR positive tumor tissue but also to target cytotoxic T lymphocytes in the TME, resulting in more effective tumor killing. (Page 4, column 1.) Sun teaches that the sumIL-2 complex results in reduced lung toxicity as measured by the onset of pulmonary edema. (Page 6, column 1; page 11, column 1.)
It would have been obvious to construct an activatable IL-2 fusion protein heterodimer according to the combined teachings of Winston and Sun. Sun teaches that a heterodimer with an activatable mutant IL-2 on one arm and a tumor-targeting antibody on the other arm delivers the IL-2 to the desired TME. The person of ordinary skill in the art would have found it obvious to configure Winston’s activatable IL-2 fusion protein according to Sun’s example because Winston is concerned with delivering IL-2 to the tumor microenvironment and Sun’s supIL-2 achieves that outcome. The skilled artisan would have expected reduced lung toxicity relative to IL-2 in such a construct because Sun demonstrates that supIL-2 does not result in pulmonary edema.
Maintenance Fees
Applicant is reminded of the requirement to pay all applicable maintenance fees on the original patent. See MPEP 1415.01.
Duty to Disclose
Applicant is reminded of the continuing obligation under 37 CFR 1.178(b), to timely apprise the Office of any prior or concurrent proceeding in which Patent No. 11,597,753 is or was involved. These proceedings would include any trial before the Patent Trial and Appeal Board, interferences, reissues, reexaminations, supplemental examinations, and litigation.
Applicant is further reminded of the continuing obligation under 37 CFR 1.56, to timely apprise the Office of any information which is material to patentability of the claims under consideration in this reissue application.
These obligations rest with each individual associated with the filing and prosecution of this application for reissue. See also MPEP §§ 1404, 1442.01 and 1442.04.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LORA E BARNHART DRISCOLL, whose telephone number is (571)272-1928. The examiner can normally be reached M-F 7:00-4:00 p.m. ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Patricia Engle, can be reached on 571-272-6660. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Lora E Barnhart Driscoll/ Patent Reexamination Specialist, Art Unit 3991
Conferees:
/KSO/
Patent Reexamination Specialist, Art Unit 3991
/Patricia L Engle/ SPRS, Art Unit 3991
1 Both references were also provided in this reissue application with an IDS on 4/3/23.
2 If the examiner had not withdrawn these aspects of the species election by permitting the shift of species, then the original-patent requirement would not be met because applicant would now be claiming non-elected subject matter in a reissue rather than having filed a continuing application of the underlying ’679 application. See MPEP 1412.01(II) (citing In re Orita, 550 F.2d 1277, 1280, 193 USPQ 145, 148 (CCPA 1977)).
3 It is likely that claim 32 was intended to depend from claim 18, not claim 1, but the examiner must consider the claims as applicant has presented them.
4 It is likely this is a typographical error for “antibody Fc region,” but the examiner must consider the claim as applicant has presented it.