DETAILED ACTION
Status of Application, Amendments and/or Claims
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The preliminary amendment of 5/5/23 has been entered in full. Claims 1, 3-8, 10-11, 15, 17 and 19 are amended. New claim 20 is added.
Claims 1-20 are pending.
Drawings
Corrected drawings in compliance with 37 CFR 1.121(d) are required because:
The instant drawings do not comply with 37 C.F.R. 1.84(U)(1), which states that partial views of a drawing which are intended to form one complete view, whether contained on one or several sheets, must be identified by the same number followed by a capital letter. Specifically, the partial views of Figure 2 are designated Figure 2A.1 through 2A.11, 2B.1 through 2B.11 and 2C.1 through 2C.11. Instead, each partial view of Figure 2 should be followed by a different letter, e.g., Figure 2A, 2B, 2C, etc. As there are more than 26 partial views, Figure 2B and/or Figure 2C should re-designated with a different number (e.g., Figure 3A, 3B, 3C, etc).
Applicants are advised to employ the services of a competent patent draftsperson outside the Office, as the USPTO no longer prepares new drawings. The corrected drawings are required in reply to the Office action to avoid abandonment of the application. The requirement for corrected drawings will not be held in abeyance.
Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d).
Applicants are reminded that once the drawings are changed to meet the separate numbering requirement of 37 C.F.R. 1.84(U)(1), Applicants are required to file an amendment to change the Brief Description of the Drawings and the rest of the specification accordingly.
Specification
The disclosure is objected to because of the following informalities:
---The Brief Description of Figure 2 in ¶ 32 does not identify each of the various “partial views” (parts) of the figure. As noted above, Figure 2 includes partial views designated Figure 2A.1 to 2A.11, 2B.1 to 2B.11 and 2C.1 to 2C.11. The Brief Description of Figure 2 should have a description of each partial view, identified by the corresponding label. Applicants should correct the labeling of the partial views as set forth above, and then update the Brief Description to identify each of the partial views.
Appropriate correction is required.
Improper Multiple Dependent Claims
Claims 11-14 are objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim should refer to other claims in the alternative only. See MPEP § 608.01(n). Specifically, claim 11 as amended is limited to “A binding molecule of claim 1” (line 1), but also refers to administering “the binding molecule according to any one of claims 1-10 to the individual” (line 6). Because line 1 is limited to claim 1, but line 6 refers to any of claims 1-10, the claim encompasses combinations of limitations referring to both of claim 1 and one of claims 2-10, and thus does not properly refer to other claims in the alternative only. Claims 12-14 each depend from claim 11 and thus incorporate the same improper form of limitations.
Accordingly, claims 11-14 have not been further treated on the merits.
Claim Objections
Claims 1-10 and 15-20 are objected to because of the following informalities:
Claim 1, starting in line 3, recites “comprising a combination of amino acid substitutions L234A, L235A, S267K, P329A (LALASKPA)”. While the term “LALASKPA” indicates that the combination of all four mutations are present, the phrase is missing a transitional phrase and conjunction. The following correction is suggested: “comprising a combination of amino acid substitutions consisting of L234A, L235A, S267K, and P329A (LALASKPA)”.
In claim 2, line 2, “SEQ ID NO” should be “SEQ ID NO:”.
In claim 7, line 1, “according claim 1” should be “according to claim 1”.
The remaining claim(s) are objected to for depending from an objected claim.
Appropriate correction is required.
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.
Claim 2 is 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 pre-AIA the applicant regards as the invention.
Claim 2, in the alternative, limits the limits the binding molecule of claim 1 to one wherein the Fc variant comprises the sequence of SEQ ID NO: 21. The specification identifies SEQ ID NO: 21 as “Human IgG1 Fc variant G237A/D265A/P329A/S267K (GADAPASK) amino acid sequence” (page 69). However, parent claim 1 has been amended to remove the alternative directed to this embodiment, and is now limited to the LALASKPA variant, which includes substitutions at residues 234, 235, 267 and 329. The amino acid sequence of SEQ ID NO: 21 does not includes substitutions at residues 234 and 235. As such, parent claim 1 does not encompass SEQ ID NO: 21 as recited in the alternative in claim 2. Therefore, claim 2 is indefinite because it is unclear how the claim can encompass SEQ ID NO: 21 when the parent claim is limited to the LALASKPA variant.
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 35 U.S.C. 112 (pre-AIA ), fourth paragraph: Subject to the [fifth paragraph of 35 U.S.C. 112 (pre-AIA )], 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.
Claim 2 is 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.
Per MPEP 608.01(n).III, “If the dependent claim does not comply with the requirements of 35 U.S.C. 112(d), the examiner should reject the dependent claim under 35 U.S.C. 112(d) rather than objecting to the claim” and “a dependent claim must be rejected under 35 U.S.C. 112(d) if it omits an element from the claim upon which it depends or it fails to add a limitation to the claim upon which it depends”.
Claim 2, in the alternative, limits the limits the binding molecule of claim 1 to one wherein the Fc variant comprises the sequence of SEQ ID NO: 21. The specification identifies SEQ ID NO: 21 as “Human IgG1 Fc variant G237A/D265A/P329A/S267K (GADAPASK) amino acid sequence” (page 69). However, parent claim 1 has been amended to remove the alternative directed to this embodiment, and is now limited to the LALASKPA variant, which includes substitutions at residues 234, 235, 267 and 329. The amino acid sequence of SEQ ID NO: 21 does not includes substitutions at residues 234 and 235. As such, parent claim 1 does not encompass SEQ ID NO: 21 as recited in the alternative in claim 2. Thus, claim 2 is of improper dependent form because it recites a limitation outside the scope of the parent claim and thus fails to include all of the limitations of the claim upon which it depends.
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 § 112, enablement
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 1-10 and 15-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while enabling for
A binding molecule comprising a human IgG1 Fc variant of a wild-type human IgG1 Fc region and one or more antigen binding domains, wherein the Fc variant comprises the amino acid sequence of SEQ ID NO: 15,
does not reasonably provide enablement for
A binding molecule comprising a human IgG1 Fc variant of a wild-type human IgG1 Fc region and one or more antigen binding domains, wherein the Fc variant comprises a combination of amino acid substitutions L234A, L235A, S267K, P329A (LALSKPA), and wherein the amino acid residues are numbered according to the EU index of Kabat.
The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is “undue” include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability in the art, 5) existence of working examples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The nature of the invention of independent claim 1, and dependent claims 2-10, is a product; specifically, a binding molecule (e.g., antibody) comprising a human IgG1 Fc variant. Claims 15-20 are directed to products related to and dependent on the limitations of the binding molecule of claim 1; a composition comprising the molecule (claims 15-16); an isolated polynucleotide encoding the molecule (claim 17); a vector comprising the polynucleotide (claim 18); and a host cell comprising the vector (claim 19) or polynucleotide (claim 20).
The instant specification teaches that it is advantageous for certain therapeutic antibodies comprising an Fc region to “decrease or even to fully remove the effector functions” (¶ 4), such as for antibodies delivery payloads or for those interfering with receptor-ligand interactions (¶ 4-5). The specification teaches that “[s]everal mutation sets were generated and compared with wildtype IgG1” including LALASKPA-IgG1 (Example 1, ¶ 211). The specification teaches that “All IgG1 antibody-Fc variants inhibit the binding to Fc gamma receptors compare to WT (SEQ ID NO 1 and 3) and little or no residual binding was measured” (¶ 216).
The specification discloses a human IgG1 Fc variant with the LALASKPA mutations as SEQ ID NO: 15, which is 217 amino acids in length (page 67). Dependent claim 2 recites this embodiment, along with SEQ ID NO: 21, which is another variant not including LALA mutations and thus not encompassed by parent claim 1 (see “Claim Rejections - 35 USC § 112(d)”). In addition, in the alternative the claim encompasses variants of SEQ ID NO: 15 “having at least 95%, 96%, 97%, 98%, or 99% homology”. A variant having at least 95% identity to SEQ ID NO: 15 includes those with up 5% of the sequence changed, or up to 21 amino acids in combination. Furthermore, parent claim 1 encompasses not just these variants, but also variants with any number of other amino acid changes in combination. The specification expressly states that “[a] "variant Fc region" or "modified Fc fragment" comprises an amino acid sequence which differs from that of a "native" or "wildtype" sequence Fc region by virtue of at least one "amino acid modification" as herein defined” (¶ 93). The term “at least one” is a range without an upper limit. As such, the “variant Fc region” of the claim 1 encompasses variants in which one or more, up to and including all 217 amino acids of the Fc region, are mutated. Thus, the claims are genus claims directed to a product comprising a genus of Fc variants that include variants with any number of mutations in addition to the LALAKSPA mutations. The genus of claim 1 and dependent claims 3-9 and 15-20 is essentially without limit because any number of changes to each sequence is encompassed, and the genus of claim 2 encompasses up to 17 out of 217 amino acids of the sequence of SEQ ID NO: 15 changed in combination.
The prior art teaches that “[m]ultiple mutation combinations in the IgG Fc have been characterized to tailor immune effector function or IgG serum persistence to fit desired biological outcomes for monoclonal antibody therapeutics”, but that “[a]n unintended consequence of introducing mutations in the Fc (particularly the CH2 domain) can be a reduction in biophysical stability which can correlate with increased aggregation propensity, poor manufacturability, and lower solubility” (see Abstract of Borrok et al, 2017. Journal of Pharmaceutical Sciences. 106: 1008-1017). The prior art also appreciates, with respect to protein mutations in general, that "[m]utations … are generally destabilizing, and can reduce protein … fitness" and "[i]n general, 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" (pg 602 of Tokuriki et al, 2009, Current Opinion in Structural Biology. 19: 596-604). The prior art also appreciates that "the range of possible SNV [single nucleotide variation] effects at the protein level are significantly greater than currently assumed by existing software prediction methods, and that correct prediction of consequences remains a significant challenge" (pg 18 of Bhattacharya et al, 2017. Plos One. 12(3): e0171355, pages 1-22 as printed).
The specification provides limited teachings in support of the claimed genus of variants. The specification describes other single substitutions, or small groups of substitutions, that can be made in an Fc domain to reduce effector function; e.g., G237A or D265A, the specification does not provide teachings of mutations that can be made in combination with the LALASKPA that correspond to what is claimed, i.e., variants in which up to 100% of the protein is mutated, and without impact the viability of the Fc domain by introducing mutations that cause aggregation or insolubility as taught by Borrok et al (2017; cited above). The specification indicates that the variants of the invention should have “a high melting temperature”, be “stable”, and “capable of being recombinantly produced at high yields and formulated to high concentrations that remain stable for prolonged periods without aggregation” (¶ 111), but fails to provide guidance as the nature and range of mutations that can be made in addition to LALASKPA and still retain these properties.
Thus, knowledge of the sequence of human IgG1 Fc region and the variant with the LALASKPA mutation (having the amino acid sequence of SEQ ID NO: 15) is not sufficient for the skilled artisan at the time of the effective filing date to predict the full scope of mutations encompassed by the claimed Fc variant that will retain biological functionality. Instead, the skilled artisan would need to make and test a representative range of mutants corresponding to the claimed scope, which encompasses in combination a vast number of mutations in the Fc region.
Due to the large quantity of experimentation necessary to generate the vast number of variants of SEQ ID NO: 15, a Fc region comprising the LALASKPA mutations and screen the same for functionality, the lack of direction/guidance presented in the specification regarding which structural features are required in order to provide such functionality, the absence of working examples beyond the LALASKPA Fc variant directed to same, the complex nature of the invention, the state of the prior art which establishes the unpredictability of the effects of mutation on protein structure and function, and the breadth of the claims, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention in its full scope.
Double Patenting
The nonstatutory double (NSDP) 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 NSDP 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 (TD) in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on NSDP 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 TD must be signed in compliance with 37 CFR 1.321(b).
The filing of a TD by itself is not a complete reply to a NSDP rejection. A complete reply requires that the TD 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 TD 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 (eTD) may be filled out completely online using web-screens. An eTD that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTDs, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-9 and 15-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 169-196 and 199-202 of co-pending application 18/035,470, filed 5/4/23, and which shares the same applicant and includes the same two inventors with the instant application. Although the conflicting claims are not identical, they are not patentably distinct from each other for the following reasons.
The instant application and the ‘470 application are each 371 applications of different PCT applications that each claim priority to the same provisional application.
Instant claim 1 encompasses a binding molecule comprising a human IgG1 Fc variant of a wild-type human IgG1 Fc region and one or more antigen binding domains, wherein the Fc variant comprises a combination of amino acid substitutions L234A, L235A, S267K, P329A (LALSKPA), and wherein the amino acid residues are numbered according to the EU index of Kabat.
Independent claim 169 of ‘470 is directed to a CD19 binding molecule that comprising (i) a set of antibody CDRs and (ii) “a first variant human IgG1 Fc region and a second variant human IgG1 Fc region forming a Fc domain, wherein the first and second variant Fc regions comprise L234, L235A, S267K, and P329A (“LALASKPA”) substitutions, wherein the amino acid residues are numbered according to the EU numbering system”. Thus, the CD19 binding molecule of claim 169 of ‘470 is fully encompassed by the binding molecule instant claim 1, and as a narrower embodiment therefore anticipates instant claim 1, and therefore the two sets of claims are not patentably distinct.
Instant claim 2 encompasses a binding molecule of claim 1 wherein the Fc variant comprises the sequence of SEQ ID NO: 15. The instant specification teaches that SEQ ID NO: 15 is the “Human IgG1 Fc variant L234A/L235A/S267K/P329A (LALASKPA)”. Thus, the variant human IgG1 Fc domain comprising the LALASKPA mutations of claim 169 of ‘470 is directed to the same sequence as SEQ ID NO: 15. Therefore, claim 2 is not patentably distinct from the claims of ‘470 for the same reasons as claim 1.
Instant claim 3 encompasses a binding molecule of claim 1 that is a human IgG1 monoclonal antibody; i.e., claim 3 further limits the binding molecule to a monoclonal antibody. The CD19 binding molecule of claim 169 of ‘470 comprises one of eight sets of antibody CDRs, and thus the binding portion of the binding molecule of ‘470 is limited to a monoclonal antibody. Therefore, claim 3 also encompasses the binding molecule of claim 169 of ‘470, and is not patentably distinct.
Instant claims 4, 6 and 7 encompass a binding molecule of claim 1 having a further property: reduced binding affinity to a Fc gamma receptor compared to a polypeptide comprising the wild-type human IgG1 Fc region, wherein the receptor is Fc gamma RIA (claim 4); reduced effector function compared to a polypeptide comprising the wild-type human IgG1 Fc region (claim 6) or binding to an antigen without triggering detectable ADCC (claim 7). Binding to the Fc gamma region triggers effector function, with the instant specification at ¶ 100 defining ADCC as a typical effector function. The instant specification provides evidence that a human IgG1 Fc variant comprising the LALASKPA mutations has such reduced binding; see ¶ 216 and Table 2 in the working examples. The instant specification further states that the variant comprising LALASKPA is “silent” (¶ 217), which is elsewhere defined as having “minimal interaction with effector cells” (¶ 109). As such, the human IgG1 Fc variant of claim 169 of ‘470 having the LALASKPA combination of mutations inherently also possesses this functionality. Therefore, instant claims 4, 6 and 7 also encompass the binding molecule of claim 169 of ‘470, and are not patentably distinct.
Instant claim 5 encompasses a binding molecule of claim 1 wherein the antigen is a cell surface antigen. CD19 is a cell surface antigen. Therefore, claim 5 also encompasses the binding molecule of claim 169 of ‘470, and is not patentably distinct.
Instant claims 8-9 and 15-20 depend from claim 1 and each further limit the binding molecule of claim 1 to embodiments that correspond to the further limitations of the CD19 binding molecule of the dependent claims of ‘470 in the following manner:
Instant Claim
Claim of ‘470
8
172
9
173
15
199
16
199
17
200
18
200
19
201
20
201
As such, the further embodiments of 8-9 and 15-20 are also anticipated by the corresponding claims of the ‘470 patent, and as such these instant claims are also not patentably distinct from the claims of ‘470.
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
Note that while the above double patenting rejection is provisional, the instant application and the ‘470 application share the same “patent term filing date”, which is 11/4/2021, taking into account any benefit under 35 U.S.C. 120, 121, 365(c), or 386(c)). Per MPEP 804.I.B.1.(b).(ii):
“If both the application under examination and the reference application have the same patent term filing date, the provisional nonstatutory double patenting rejection made in each application should be maintained until it is overcome. Provisional nonstatutory double patenting rejections are subject to the requirements of 37 CFR 1.111(b). Thus, applicant can overcome a provisional nonstatutory double patenting rejection by filing a reply that either shows that the claims subject to the rejection are patentably distinct from the claims of the reference application, or includes a compliant terminal disclaimer under 37 CFR 1.321 that obviates the rejection. If the reply is sufficient, the examiner will withdraw the nonstatutory double patenting rejection in the application in which it was submitted."
Thus, per MPEP 804, the provisional double patenting rejection set forth above should be maintained in the instant application unless overcome as indicated therein.
Claims 1-8 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 136-142 of co-pending application 18/035,472, filed 5/4/23, and which shares the same applicant and includes the same two inventors with the instant application. Although the conflicting claims are not identical, they are not patentably distinct from each other for the following reasons.
The instant application and the ‘472 application are each 371 applications of different PCT applications that each claim priority to the same provisional application.
Instant claim 1 encompasses a binding molecule comprising a human IgG1 Fc variant of a wild-type human IgG1 Fc region and one or more antigen binding domains, wherein the Fc variant comprises a combination of amino acid substitutions L234A, L235A, S267K, P329A (LALSKPA), and wherein the amino acid residues are numbered according to the EU index of Kabat.
Independent claim 136 of ‘472 is directed to a combination comprising a CD19 binding molecule comprising three different antigen-binding molecules and a Fc domain. Dependent claims 138 and 139 limit the combination of claim 136 to one with a Fc domain that has a first variant human IgG1 Fc region and a second variant human IgG1 Fc region forming a Fc heterodimer (claim 138), and further wherein the first and second variant Fc regions comprise L234, L235A, S267K, and P329A (“LALASKPA”) substitutions, wherein the amino acid residues are numbered according to the EU numbering system (claim 139). Thus, the CD19 binding molecule of the combination claims 136 and 138-139 of ‘472 is fully encompassed by instant claim 1, and as a narrower embodiment therefore anticipates instant claim 1, and therefore the two sets of claims are not patentably distinct.
Instant claim 2 encompasses a binding molecule of claim 1 wherein the Fc variant comprises the sequence of SEQ ID NO: 15. The instant specification teaches that SEQ ID NO: 15 is the “Human IgG1 Fc variant L234A/L235A/S267K/P329A (LALASKPA)”. Thus, the variant human IgG1 Fc domain comprising the LALASKPA mutations of claims 136 and 138-139 of ‘472 is directed to the same sequence as SEQ ID NO: 15. Therefore, claim 2 is not patentably distinct from the claims of ‘472 for the same reasons as claim 1.
Instant claim 3 encompasses a binding molecule of claim 1 that is a human IgG1 monoclonal antibody; i.e., claim 3 further limits the binding molecule to a monoclonal antibody. The CD19 binding molecule of claim 136 of ‘472 comprises a set of antibody CDRs, and thus is limited to a monoclonal antibody. Therefore, claim 3 also encompasses the binding molecule of claims 136 and 138-139 of ‘472, and is not patentably distinct.
Instant claims 4, 6 and 7 encompass a binding molecule of claim 1 having a further property: reduced binding affinity to a Fc gamma receptor compared to a polypeptide comprising the wild-type human IgG1 Fc region, wherein the receptor is Fc gamma RIA (claim 4); reduced effector function compared to a polypeptide comprising the wild-type human IgG1 Fc region (claim 6) or binding to an antigen without triggering detectable ADCC (claim 7). Binding to the Fc gamma region triggers effector function, with the instant specification at ¶ 100 defining ADCC as a typical effector function. The instant specification provides evidence that a human IgG1 Fc variant comprising the LALASKPA mutations has such reduced binding; see ¶ 216 and Table 2 in the working examples. The instant specification further states that the variant comprising LALASKPA is “silent” (¶ 217), which is elsewhere defined as having “minimal interaction with effector cells” (¶ 109). As such, the human IgG1 Fc variant of claim 169 of ‘472 having the LALASKPA combination of mutations inherently also possesses this functionality. Therefore, claims 4, 6 and 7 also encompass the binding molecule claims 136 and 138-139 of ‘472, and are not patentably distinct.
Instant claim 5 encompasses a binding molecule of claim 1 wherein the antigen is a cell surface antigen. CD19 is a cell surface antigen. Therefore, claim 5 also encompasses the binding molecule of claims 136 and 138-139 of ‘472, and is not patentably distinct.
Instant claim 8 depends from claim 1 and further limits the binding molecule to one that is a multi-specific binding molecule comprising binding domains for two or more antigens (claim 8). The CD19 binding molecule of the combination of claims 136 and 138-139 includes three antigen-binding molecules that bind to three different antigens: CD19, CD3 and CD2. As such, claim 8 encompasses the binding molecule of claims 136 and 138-139 of ‘472, and is not patentably distinct.
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
Note that while the above double patenting rejection is provisional, the instant application and the ‘472 application share the same “patent term filing date”, which is 11/4/2021, taking into account any benefit under 35 U.S.C. 120, 121, 365(c), or 386(c)). Per MPEP 804.I.B.1.(b).(ii):
“If both the application under examination and the reference application have the same patent term filing date, the provisional nonstatutory double patenting rejection made in each application should be maintained until it is overcome. Provisional nonstatutory double patenting rejections are subject to the requirements of 37 CFR 1.111(b). Thus, applicant can overcome a provisional nonstatutory double patenting rejection by filing a reply that either shows that the claims subject to the rejection are patentably distinct from the claims of the reference application, or includes a compliant terminal disclaimer under 37 CFR 1.321 that obviates the rejection. If the reply is sufficient, the examiner will withdraw the nonstatutory double patenting rejection in the application in which it was submitted."
Thus, per MPEP 804, the provisional double patenting rejection set forth above should be maintained in the instant application unless overcome as indicated therein.
Art of Note
No prior art has been identified that teaches the specific LALASKPA combination of four amino acid mutations required by the Fc variant of the claimed binding protein. The LALASKPA combination requires L234A, L235A, S267K and P329A substitutions.
The following articles, patents, and published patent applications were found by the Examiner during the art search while not relied upon for a rejection are considered pertinent to the instant application:
---Schlothauer et al (2016. Protein Engineering, Design & Selection. 29(10): 457-466; cited on the 5/5/23 IDS). This reference teaches a Fc variant with the L234A and L235A substitutions (known as LALA) in combination with a P329G substitution, which is a different mutation at residue 329. Schlothauer further teaches the superiority of the P329G over the previously known P329A mutation: “Introducing instead a P329G, rather than a P329A, mutation further increases the inertness of the Fc portion, and the combination of this P329G with LALA results in a complete silencing of the FcγR binding” and “For the FcγRs IIa, IIb and IIIa, there is a clear difference between P329A and P329G” (page 464). Thus, this reference teaches away from use of the P329A mutation in place of the P329G mutation. Therefore, in view of the teachings of this reference, there is no motivation for the skilled artisan to use the P329A mutation instead of the P329G mutation in combination with the LALA mutations. Furthermore, because the combination of LALA and P329G produces “complete silencing of the FcγR binding”, there is also no motivation to include any further silencing mutations such as the S267K substitution also required by the instant claims.
---Moore et al (2019. Methods. 154: 38-50; cited on the 5/5/23 IDS). This reference teaches a Fc variant with a combination of five mutations including E233P, L233V, L235A, G236del and S267K (page 45). This combination is described as “an IgG1 variant that combined the IgG2 lower hinge substitution with an additional CH2 substitution (S267K) at a surface residue previously shown to dramatically modulate FcγRII affinity … The FcγR binding of the resulting Fc variant mAb (E233P/ L234V/L235A/G236del/S267K) was compared to that of native IgG1 by surface plasmon resonance. As seen in Fig. 7A, binding to Fcγ receptors I, IIa, IIb, and IIIa could not be observed” (page 45). First, this combination includes a L234V mutation instead of a L234A mutation required by the instant claims. Second, this combination is described throughout as “Fc-silenced” or “Fc-silencing” (e.g., Figure 7 on page 43; page 48), and Moore does not include or anywhere reference the previously identified P329G or P329A mutations. In view of the complete silencing by the combination taught by Moore, there is no motivation to include an additional mutation at the 329 residue as taught by the prior art.
---U.S. Patent Application Publication 2023/0302155, published 9/28/23, filed 8/20/21, and claiming priority to provisional applications 63/154,609, filed 2/26/21 and 63/068,876, filed 8/21/20. The ‘155 publication teaches the LALASKPA combination of mutations (e.g., at ¶ 30). However, while the ‘155 publication claims priority to one provisional application (‘876) with a filing date (8/21/20) that is earlier than the earliest claimed priority date than that of the instant application (11/6/20), a review of this priority document indicates that it does not teach the LALASKPA combination of mutations, or even the S267K individual mutation. As such, the ‘155 publication does not merit priority to the 8/21/20 for subject matter employing an Fc variant comprising the LALASKPA combination of mutations.
Conclusion
No claims are allowable.
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/ZACHARY C HOWARD/Primary Examiner, Art Unit 1674