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 .
DETAILED ACTION
Status of the Claims
1. Claims 1-15 are the original claims filed 6/21/2023. In the Preliminary Response of 6/21/2023, Claims 3-12 and 14-15 are amended. In the Response of 6/15/2026, Claims 1-3 and 6-7 are amended.
Claims 1-15 are the pending claims.
The Office Action is final.
Priority
2. USAN 18/268,840, filed 06/21/2023, is a National Stage entry of PCT/EP2021/ 086735, International Filing Date: 12/20/2021, claims foreign priority to EP 20315503.1, filed 12/22/2020.
Information Disclosure Statement
3. As of 8/13/2026, a total of one (1) IDS is filed: 6/21/2023. The corresponding initialed and dated 1449 form is considered and of record.
Withdrawal of Objections
Specification
4. The objection to the disclosure because of informalities is withdrawn. Both clean and marked-up copies of the specification are filed.
a) The specification is amended to rectify the improper use of the term MALS, BiaCore, MassHunter, PLRP-S, ASTA, Superdex, MabSelect, Tris, Triton, which is a trade name or a mark used in commerce.
b) The specification is amended to correct a typographical error for FcRn (or FcGRLN).
c) The specification is amended on p. 18, line 12 to disclose “Example 1 employs the…”
Claim Objections
5. The objection to Claims 1-3 and 6-7 because of informalities is withdrawn.
The objections for each of (a)-(e) in the O.A. of are withdrawn in view of the amendment of the claims.
Rejections Withdrawn-in-part/ Maintained-in-part
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.
Written Description
6. The rejection of Claims 1-15 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 is:
Withdrawn-in-part for claims 6-7: Claims 6 and 7 are amended to define the assay (SPR) used to determine affinity for the corresponding antigen for the molecule of claim 1.
Maintained-in-part for claims 1-15: the negative proviso for the N-terminal portion for each polypeptide is not clarified by the arguments of the Applicant; and the claimed structure for the C-terminus of each of the 2 polypeptides linked by at least two covalent bonds is not clarified by the arguments of the Applicant.
(A) Applicants allege specification describes embodiments that do not include the full antibody hinge region at either the N-terminus or the C- terminus. The disclosure encompasses a range of structures in which the interchain linkage is defined by the absence of N-terminal disulfide bonding and the presence of C-terminal covalent bonding.
Response to the Arguments
N-terminal portion of the molecule
The N-terminal portion of each polypeptide is defined in claim 1 by a negative proviso (i.e., are not linked). The use of a negative limitation is used to define the invention in terms of what it is not, rather than distinctly and particularly claiming the structure comprising the N-terminus for each of the two polypeptides that is supported (and enabled) in the specification. Under MPEP 2173.05(i) “Any negative limitation or exclusionary proviso must have basis in the original disclosure.”
At least in claims 6 and 7, the N-terminal structure is implied by its functional attributes (i.e., compared to the same molecule comprising an antibody hinge region located N- terminally to the portion of each polypeptide which forms the Fc region). The limitation absent a structure with a required function does not satisfy the structure/ function correlation under the written description guidelines under MPEP 2163 (II)(3)(a)(ii) stating in part:
“The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus (see i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021) ( "[T]he written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention. Ariad, 598 F.3d at 1353–54 ('[T]he purpose of the written description requirement is to ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor's contribution to the field of art as described in the patent specification.' (internal quotation marks omitted).").”
The range of hinge structures on pp. 11-12 of the specification are not substantiated by intrinsic or extrinsic evidence showing the correlation with the functional properties recited in claims 6 and 7 for the molecule of claim 1. Applicants’ assertion that the range of hinges is applicable to the genus of N-termini for each of the two polypeptides is not substantiated by a preponderance of the evidence. MPEP 706(I): “The standard to be applied in all cases is the “preponderance of the evidence” test. In other words, an examiner should reject a claim if, in view of the prior art and evidence of record, it is more likely than not that the claim is unpatentable.”
The range of hinge structures shown in the drawings are depicted in:
Fig 1B “(B) Schematic view of an effector-less Fc region according to the present invention. The hinge region, located N-terminally of the Fc region, was removed, its sequence was shifted to the C-terminus of the Fc region. Moreover, the CH1 domain was connected to the CH2 domains via a linker sequence. Consequently, this new arrangement completely eliminates the binding sites for FcγRs and C1q.
Fig 2 “Mab06 is an Fc IgG1 according to the present invention (labeled as “upside-down”) with the sequence of the hinge region transferred to the C-terminus and no linker sequence between CH1 and CH2 domains. Mab07 is an Fc IgG1 according to the present invention (labeled as “upside-down”) further including a 19GS-linker between CH1 and CH2 domains.
[0115] The concept of Fc molecules according to the present invention was tested for the anti-TNF antibody adalimumab. We created two different versions of an Fc adalimumab according to the present invention (FIG. 2, mab06 (heavy chain SEQ ID NO: 10) and mab07 (heavy chain SEQ ID NO: 11)). These two constructs differed only in the length of the linker replacing the hinge region. For comparison purposes, Fc-backbone variants known to have silenced effector functions were made as well (FIG. 2, mab02, mab04, mab05). The Fab was the same in all constructs. All antibodies were transiently expressed in CHO or Hek293 cells and purified using a two-step purification procedure. Interestingly, the highest yields were obtained with the Fc variants according to the present invention (Tab. 1).
As regards the molecule corresponding to claims 1 and 6 for SPR affinity to different FcRs, those data correspond to the Mab 04, Mab06 and Mab07 prototypes derived from the same antibody, the same anti-TNF antibody, adalimumab:
[0042] “FIG. 6. SPR-affinity measurements of the different antibodies to different FcRs. For interaction analysis the FcRs were immobilized on the sensor chip. The sensograms show the binding profiles of the different antibodies at different concentrations. Mab06 is labeled “ud-IgG1”; Mab07 is labeled “ud-IgG1 (19GS).”
The IgG1 E269R, K322A in Fig 6 seemingly corresponds to mab04 but that information is not clear from the figure legend or the figure.
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Moreover, none of the residues for IgG1 E269R, K322A correspond to those the species instant claimed: P238C and L328C; S267C and A327C; and V240C and I332C.
What is clear from Fig 2 is that mab06 and mab07 are not shown as having Fc silencing mutations in the CH2 domain in combination with the absence of N-terminal disulfide bonds and the presence of C-terminal covalent bonds.
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Most notably and based on the prototypes tested for this series of experiments (Example 1), there is not a single prototype that corresponds to anything but an IgG1, and most importantly, there is no single prototype that corresponds to having all of the features of instant claim 1 and 6. The data are inconclusive with respect to the structure/function correlation for the full scope and breadth of instant claims 1-15, and therefore do not provide sufficient written description support for the claimed invention.
As regards the molecule corresponding to claims 1 and 7 for affinity to protein A, those data for protein A binding are not discernable from the specification as to the methods of characterization. Applicants are required to identify the specific assay used in the specification comprising a protein A chromatography step to evaluate the molecule of the invention as claimed in claim 7.
As regards the molecule corresponding to claims 1 and 7 for affinity to FcRn, those data correspond to the Mab 04, Mab06 and Mab07 prototypes derived from the same antibody, the same anti-TNF antibody, adalimumab and shown in Fig 6.
Most notably and based on the prototypes tested for this series of experiments, there is not a single prototype that corresponds to anything but an IgG1, and most importantly, there is no single prototype that corresponds to having all of the features of instant claim 1 and 7. The data are inconclusive with respect to the structure/function correlation for the full scope and breadth of instant claims 1-15, and therefore do not provide sufficient written description support for the claimed invention.
C-terminal portion of the molecule
“covalent bonds”: the specification does not elaborate or provide relevant teaching on what other type of covalent bond can be applied to the overall structure of the molecule. Claim 4 identifies disulfide bonds from amongst an infinite genus of covalent bonds much less the overall structure within in which they are comrpised.
Most notably and based on the prototypes tested for this series of experiments (Example 1), there is not a single prototype that corresponds to anything but an IgG1, and most importantly, there is no single prototype that corresponds to having all of the features of instant claim 1. The data from Example 1 are inconclusive with respect to the structure/function correlation for the full scope and breadth of instant claims 1-15, and therefore do not provide sufficient written description support for the claimed invention.
(B) Applicants allege different GLP1-receptor agonist (RA) Fc fusion proteins (GLP1-Fc12, GLP1-Fc13, and GLP1-Fc14) that were constructed using Fc variants having a shortened version of the hinge region, including a linkage by two disulfide bonds, located at the C-terminus; the GLP1-RA Fc fusion proteins-GLP1-Fc12, GLP1-Fc13, and GLP1-Fc14-exhibited increased thermostability. See Specification, p. 28, Fig. 9.
Response to Arguments
AS regards GLP1-Fc12, the prototype does not meet or satisfy the written description of the invention of claim 1.
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The prototype is dispositive to the requirement that the CH2-domain contain an additional internal disulfide bond where none is shown.
As regards GLP1-Fc13, the prototype structure resembles the instant claimed molecule and comprises P238C/L328C internal disulfide bond for the CH2 domain
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but is not shown to have reduced affinity for the FcRs (Claim 6) nor an affinity for protein A and/or FcRn that is the same as the same molecule having an antibody hinge. The specification does not teach the ordinary artisan how to make the fusion protein for Fc013 or Fc014, specifically at [0123] To evaluate the Fc format according to the present invention for a peptide Fc fusion protein and to test in vivo functionality, we used GLP1-receptor agonist (RA) Fc fusion proteins. Thus, we fused a human GLP1-RA via a peptide linker to an IgG4 Fc region (FIG. 9, GLP1-Fc01 and 04) or to an IgG1 Fc region FIG. 9, GLP1-Fc02, 05-014). FIG. 9 shows an overview of the different GLP1-RA-Fc fusion protein variants.”
The identity of the IgG1 Fc region is not defined in the specification as filed. It is inconclusive whether the IgG1 Fc domain for the fusion protein is the same as that from Example 1. The POSA cannot reproduce or replicate the invention based in the deficiency in the disclosure of the specification.
As regards GLP1-Fc14, the prototype structure resembles the instant claimed molecule and comprises S267C/A327C internal disulfide bond for the CH2 domain
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but is not shown to have reduced affinity for the FcRs (Claim 6) nor an affinity for protein A and/or FcRn that is the same as the same molecule having an antibody hinge. The specification does not teach the ordinary artisan how to make the fusion protein for Fc013 or Fc014, specifically at [0123] To evaluate the Fc format according to the present invention for a peptide Fc fusion protein and to test in vivo functionality, we used GLP1-receptor agonist (RA) Fc fusion proteins. Thus, we fused a human GLP1-RA via a peptide linker to an IgG4 Fc region (FIG. 9, GLP1-Fc01 and 04) or to an IgG1 Fc region FIG. 9, GLP1-Fc02, 05-014). FIG. 9 shows an overview of the different GLP1-RA-Fc fusion protein variants.”
The identity of the IgG1 Fc region is not defined in the specification as filed for Example 2. It is inconclusive whether the IgG1 Fc domain for the fusion protein is the same as that from Example 1. The POSA cannot reproduce or replicate any one of the prototypes, GLP1-Fc12, GLP1-Fc13, and GLP1-Fc14, much less the instant claimed invention based in the deficiency in the disclosure of the specification as filed.
Examiner’s comments
The disclosure is limited to testing a single “active moiety” or “antigen binding moiety” (GLP1-R) in a Fc fusion construct that is otherwise not reproducible because of the paucity of detail in the materials/methods describing the generic claimed Fc region of the molecule in the application at the time of filing.
The phrase “additional disulfide bonds” identified by paired residues according to EU numbering for the engineered Fc domains: P238C and D265C; and V240C and I332C, are not correlated with any single prototype of the specification nor that that can be reproduced.
Applicants’ allegation that “the GLP1-RA Fc fusion proteins-GLP1-Fc12, GLP1-Fc13, and GLP1-Fc14 exhibited increased thermostability” is incongruous with the claimed molecule where thermostability is not a required function. Moreover, the additional internal disulfide bond in the CH2 domain for GLP1-Fc13 and GLP1-Fc14 appears to be irrelevant to conferring increased thermostability because GLP1-Fc12 contains no additional internal disulfide bond in the CH2 domain.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through establishment of a structure-function correlation (by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics) or through a sufficient description of a representative number of species. Either is considered sufficient to show the applicant was in possession of the claimed genus.
The instant specification fails to describe a representative number of species to provide adequate written description of the claimed genus as per MPEP § 2163. While the specification provides general descriptions of how to make polypeptides comprising engineered Fc regions, the examples are limited for the species meeting the full breath and scope of the structure much less the even more limited function required by the claims.
Conclusion
The POSA could reasonably conclude that because the specification is insufficient in data that support Applicant being in possession of the full breadth and scope of the invention, the claims do not meet the requirements under written description.
The rejection is maintained.
Rejections Maintained
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
7. The rejection of Claim(s) 1-2 and 4-15 under 35 U.S.C. 103 as being unpatentable over Li et al (USPN 9518132 B2; issued 2016-12-13) in view of Bramhill et al (US 9156917 B2; issued 2015-10-13) is maintained.
A) Applicants allege Li discloses in its figures antibody constructs in which the VH and VL together with the hinge are located C-terminally of the CH2 and CH3 regions. The constructs shown by Li differ fundamentally from the constructs exemplified in the present application. The combination of Li and Bramhill does not teach or suggest an Fc architecture in which the two polypeptides are linked by covalent bonds located C-terminally to the Fc region, such that these bonds define the interchain linkage between the Fc chains. Rather, Li discloses constructs in which hinge-like sequences function as linkers to attach antigen-binding domains, not as covalent interchain linkages between Fc polypeptides.
Response to Arguments
Li teaches molecules comprising two polypeptides that form an antibody Fc region, where the two polypeptides are linked by at least 2 covalent bonds located C-terminal to each of the Fc regions, where the two polypeptides are not linked by a disulfide bond N-terminal to each the Fc regions, and where each polypeptide comprises a CH2 and CH3 domain in Figure 2.
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. The figure legend for Figure 2 specifically refers to a hinge or hinge-like structure in the C-terminus for each of the polypeptides comprising the CH2-CH3 Fc region and the advantages of the C-terminal feature:
“FIG. 2: Comparison of conventional antibody configuration (left panel) and DISCObody basic configuration (right panel). In DISCObody (right panel), CH2CH3 and a C-terminus flexible linker (or hinge) sequence containing cysteine residue(s) is fused to the N-terminus of a Fab structure. CH2CH3 dimerization facilitates the hinge cysteine residue(s) to form interchain disulfide bonds. The formation of the disulfide bond tethers the antigen binding regions of the two Fabs that are close in space and restricts the freedom of the orientation of antigen binding regions. Consequently, the apparent antigen binding becomes monovalent or in case both antigen binding regions can simultaneously bind to antigen targets, the resultant target orientation can be locked into a non-activating conformation.”
Li teaches the advantage of removing disulfide bonds at the N-termini of the polypeptides reduces FcR binding:
“Because the hinge sequence including the disulfide bonds N-terminus of the Fc structure in this novel modality is deleted, the FcγR binding of the DISCObody is greatly reduced. Therefore the DISCObody based on this modality do not cross link cell surface receptors and activate them.”
Li teaches the advantage of reducing Fcgamma R binding is to increase drug efficacy:
“In yet another aspect, the DISCObody modality lack or at least have significantly reduced FcγR binding and therefore do not crosslink cell surface receptors. These properties are necessary for better efficacy as opposed to other antibody formats when agonistic activity is deleterious to the overall drug efficacy.”
Li teaches the role of CH2 in triggering an immune response:
“The CH2 and the CH3 domains, located at the C-terminals of the stem of the Y, are responsible for interacting with effector molecules such as Fc receptor and complement Clq, which interaction triggers immune responses against the antigen which is bound to the VL and VH domain.”
Li does not require the deletion of the CH2 region in any of its disclosure but appreciates effectorless Fc regions.
The combination of Li and Bramhill provide the motivation to make and use an engineered antibody by modifying a CH2 domain that is critical to the stability of the molecule and to the extent that the FcRn binding activity is not interfered. The combination of Li and Bramhill provide the motivation advise the necessity of reducing FcgammaR binding, maintaining FcRn binding, and avoiding crosslinking by the rearranged position of the hinge region to be C-terminal to the CH2-CH3 portion of the Fc domain. Li teaches and provides a predictable and reasonable expectation of success in view of Bramhill for generating antibody modalities which will not activate target receptors upon binding and in the meantime offer improved profiles on product stability, safety and manufacturability.
The rejection is maintained.
Conclusion
8. No claims are allowed.
9. THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
10 Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached Mon-Fri 9 AM-5 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu Julie can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LYNN A BRISTOL/Primary Examiner, Art Unit 1643
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