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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 01/14/2026 has been entered.
Status of the Claims
Claims 1 – 2, 5 – 8, 12, 16, 24 – 25, 31, and 57 – 59 were pending. Claims 1, 5 – 7, 16 have been amended, and claim 8 has been canceled. Claims 1 – 2, 5 – 7, 12, 16, 24 – 25, 31, and 57 – 59 are currently pending and are the subject of this Office Action.
Claim Objections
Claim 1 is objected to because of the following informalities: The abbreviations “CSF” is used in claim 1 without defining the acronym. At the first use in the claims, the abbreviation should be written out in expanded form to improve clarity and readability of the claims. Appropriate correction is required.
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.
Previous rejection, withdrawn: claims 1 – 2, 8, 12, 16, 31, and 57 – 59 were rejected under 35 U.S.C. 103 as being unpatentable over PARDRIDGE (Pardridge, W.M. Delivery of Biologics Across the Blood–Brain Barrier with Molecular Trojan Horse Technology. BioDrugs 31, 503–519 (2017); see PTO-892: Notice of References Cited of 09/10/2024) in view of VISWANATHAN (US 2018/0037634 A1, published 02/08/2018; see PTO-892 of 09/10/2024).
In view of the claim amendments in the reply of 01/14/2026, this rejection is withdrawn.
New rejection, necessitated by claim amendments: claims 1 – 2, 5 – 7, 12, 16, 24 – 25, 31, and 57 – 59 are rejected under 35 U.S.C. 103 as being unpatentable over DEVIDZE (WO 2018/151821 A1, published 08/23/2018; see PTO-892 of 09/10/2024) in view of VISWANATHAN (US 2018/0037634 A1, published 02/08/2018; see PTO-892 of 09/10/2024) and IGAWA 2 (US 2014/0255398 A1, published 09/11/2014; see PTO-892: Notice of References Cited submitted with this Office Action).
The present application is directed to a method of treating a neurological disorder comprising intravenously administering an antibody or an Fc conjugate comprising a modified IgG Fc to a subject in need thereof, wherein the antibody or the Fc conjugate is active in an in vitro transcytosis assay, wherein the in vitro transcytosis assay comprises cells that express FcRn, wherein the antibody or the Fc conjugate crosses the subject's blood-brain barrier into the CSF or central nervous system of the subject and wherein the modified IgG Fc comprises the mutations M252Y, N434Y, T307Q, and Q311A as numbered by EU numbering.
DEVIDZE is directed to anti-α-synuclein antibodies, therapeutic compositions comprising the antibodies, and methods of using the antibodies to treat synucleinopathies, a group of a type of neurodegenerative diseases. See Abstract and p. 1, Background, first paragraph. DEVIDZE discloses methods of delivering an antibody to the brain, with some antibodies having increased brain exposures, and where the antibody crosses the BBB. See p. 89, second paragraph, paragraph bridging pp. 95-96 and p.140, last paragraph. DEVIDZE teaches that preferred routes of administration for its disclosed antibodies include intravenous. See p. 94, last paragraph.
DEVIDZE teaches antibodies that have an engineered Fc region that increase binding to FcRn and/or improve pharmacokinetic properties which include substitutions at positions 434Y, 307Q, 252Y, 311A. Thus, DEVIDZE renders the Fc mutations of present claims 1 and 5 – 7 obvious. See p. 69, last paragraph – p. 70, first paragraph. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of Americav.Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985)”. See MPEP 2144.05 (I) and (II).
VISWANATHAN is directed to polypeptides, such as antibody molecules and fusion proteins, comprising an Fc region, that can be used to treat, prevent, and/or diagnose disorders, such as primary central nervous system (CNS) lymphoma, brain tumor (e.g., astrocytomas, brain stem glioma, central nervous system atypical teratoid/rhabdoid tumor, central nervous system embryonal tumor, central nervous system germ cell tumor, craniopharyngioma, or ependymoma), and germ cell tumor (e.g., central nervous system tumor, . . ). See abstract and paragraphs 0293 and 0348.
VISWANATHAN teaches its disclosed antibody with a pharmaceutically acceptable carrier that is suitable for intravenous, administration (e.g., by injection or infusion). . See paragraph 0311. VISWANATHAN also discloses an IgG Fc structure and its Fc-FcRn interaction and that the claimed polypeptide increases mucosal uptake (and thus activity) as determined by a transcytosis assay. See claim 4.
VISWANATHAN teaches that “IgG and albumin are internalized into vascular endothelial cells through pinocytosis. The pH of the endosome is 6.0, facilitating association with membrane-bound FcRn. The contents of endosomes can be processed in one of two ways: either recycling back to the apical cell membrane or transcytosis from the apical to the basolateral side. IgG not associated with FcRn is degraded by lysosomes. While not wishing to be bound by theory, it is believed that FcRn interaction with IgG is mediated through Fc. The binding of Fc to FcRn is pH specific, e.g., no significant binding at pH 7.4 and strong binding in acidic environment.” See paragraphs 0245 – 0246.
Thus, VISWANATHAN suggests that FcRn can facilitate transcytosis, which is the movement from the apical [blood] to the basolateral [brain] side. VISWANATHAN teaches a polypeptide with an Fc region with a mutation that increases binding affinity for a neonatal Fc receptor (FcRn). See claim 1. VISWANATHAN also discloses an IgG Fc structure and its Fc-FcRn interaction and that the claimed polypeptide increases mucosal uptake (and thus activity) as determined by a transcytosis assay. See claim 4. According to the present specification, the transcytosis assay consists of MDCK II cells that were transfected to express human FcRn (paragraph [000202], p. 53], and thus secretes FcRn as a result of the transfection. VISWANATHAN discloses FcRn-expressing cells obtained by transient transfection of FcRn alpha and β2m and that the cells were used to perform a cell-based competition assay in order to determine Fc mutants that bound FcRn with improved binding. See Example 3, paragraph [0474]. Furthermore, VISWANATHAN discloses the Fc mutations 252Y and 434Y. See paragraph [0083], claim 15, and claim 17.
IGAWA 2 is directed to the discovery that in living organisms that have received an antigen-binding molecule containing an antigen-binding domain whose binding activity to an antigen changes depending on ion concentration conditions and containing an FcRn-binding domain having FcRn-binding activity in a neutral pH range, immune responses to the antigen are induced. See abstract. IGAWA 2 teaches the Fc variant F261 having the mutations M252Y/T307Q/Q311A/N434Y. See TABLE 5-7. Furthermore, IGAWA 2 teaches that the disclosed polypeptide (e.g., an antibody molecule or fusion protein) described herein, formulated together with a pharmaceutically acceptable carrier and that the carrier can be suitable for intravenous, intramuscular, subcutaneous, parenteral, rectal, spinal or epidermal administration (e.g., by injection or infusion). See paragraphs 0310 – 0311.
Thus, because DEVIDZE teaches an antibody that crosses the blood-brain barrier; DEVIDZE and VISWANATHAN each teaches a method of treating a neurological disorder by intravenously administering an antibody or an Fc conjugate comprising a modified IgG Fc to a subject in need thereof; VISWANATHAN teaches that the antibody or the Fc conjugate is active in an in vitro transcytosis assay, wherein the in vitro transcytosis assay comprises cells that express FcRn; and IGAWA 2 teaches an Fc variant having the exact mutations M252Y, N434Y, T307Q, and Q311A, it would have been obvious to one having ordinary skill in the art to combine the teachings of DEVIDZE, VISWANATHAN, and IGAWA 2 to arrive to the inventions of present claims 1 and 5 – 7. There would have been a reasonable expectation of success considering that a modified Fc having the mutations M252Y, N434Y, T307Q, and Q311A is known in antibodies used to successfully treat neurological disorders, as evidenced by the applied prior art.
Regarding claim 2, VISWANATHAN discloses that the polypeptide can be used to treat various neurological disorders, such as a brain tumor. See paragraphs [0347] – [0350].
Regarding claim 12 and 16, VISWANATHAN discloses that the polypeptide comprising an Fc region has a higher binding affinity (e.g., a lower dissociation constant (Kd)) for an FcRn at a pH between 6.0 and 6.5 (e.g., at pH 6.0), e.g., at least 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, ,15, 20, or 50-fold higher, than the binding affinity at a pH between 7.0 and 7.4 (e.g., at pH 7.4). See paragraph [0009].
Regarding claims 24 and 25, DEVIDZE discloses an antibody targeting the brain antigen alpha-synuclein (found in line 4 of claim 25).
Regarding claims 31 and 57, VISWANATHAN discloses that the antibody molecule can be bound to a substance, e.g., a toxin or moiety (e.g., a therapeutic drug; a compound emitting radiation; molecules of plant, fungal, or bacterial origin; or a biological protein (e.g., a protein toxin) or particle (e.g., a recombinant viral particle, e.g., via a viral coat protein) (see paragraph [0196]) or can be derivatized or linked to another functional molecule (e.g., another peptide or protein), such as a detectable agent (see paragraph [0197]).
Regarding claim 58, VISWANATHAN discloses that the Fc region can be fused to a peptide (e.g., a therapeutic peptide), a ligand (e.g., a ligand that activates upon binding with a cell surface receptor), a signaling molecule, the extracellular domain of a receptor, or a bait protein (e.g., used to identify a binding partner, e.g., in a protein microarray). See paragraph [0208].
Regarding claim 59, VISWANATHAN discloses a fusion protein comprises the extracellular domain of CTLA-4 fused to the Fc region of human IgG1. See paragraph [0213].
Response to Arguments
On page 7, first paragraph – second paragraph of the reply of 01/14/2026, Applicant argues that “Pardridge clearly discloses that the ‘neonatal Fc receptor (FcRn) is expressed at the BBB ... and mediates the reverse transport of IgG from brain back to blood, but does not mediate the uptake of IgG from blood to brain.’ Page 508, right column, first paragraph. This is in direct contravention of the amendment to claim 1, which specifies delivery of an antibody to the CNS or central nervous system of the recited subject by intravenous administration. As such, a person of ordinary skill in the art would not start with Pardridge in order to develop a method of treating neurological disorders in a subject by modifying an antibody's Fc region as recited in claim 1. Visnawathan does not remedy this defect.”
Applicant’s arguments are not persuasive because PARDRIDGE teaches the transportation of endogenous or wildtype (WT) IgG across the BBB and not of an IgG with a modified Fc. Nonetheless, VISWANATHAN teaches that a modified IgG Fc can bind FcRn with higher affinity than the WT Fc and can be used in pharmaceuticals targeting the CNS. VISWANATHAN teaches that modifying the Fc domain of an antibody so that it binds to FcRn more effectively results in an antibody that crosses the BBB. See discussion above.
On p. 7, second paragraph, Applicant argues that “Visnawathan, cited for its disclosure of various antibody Fc mutations, does not teach or suggest antibody Fc mutations to promote crossing the blood-brain barrier. Instead, to the extent Visnawathan discusses barriers at all, it states that ‘FcRn transports IgG across different cellular barriers such as the mucosal epithelium lining the intestine and the alveolar surfaces’ (paragraphs [0263] and [0518]). Thus, the combination of Pardridge and Visnawathan points away from modifications of the antibody Fc region such that the antibody can cross the blood-brain barrier in order to deliver antibodies to the CNS or nervous system after intravenous administration, as claimed in amended claim 1.”
Applicant’s argument is not persuasive because VISWANATHAN teaches that IgG is transported across the BBB via its interaction with FcRn and VISWANATHAN teaches that modifying the Fc region (and its pH) of IgG can increase its affinity to FcRn. See discussion above.
On p. 7, last paragraph, Applicant argues that “Visnawathan never discloses or suggests the specific combination of four mutations recited in amended claim 1. Visnawathan discloses many single mutations, and many multiple mutations (see, e.g., Table 1 at pages 16-18), but never discloses the four mutations together. Moreover, Visnawathan never discloses the M252Y mutation with any Q311 mutation. Many sets of actually-tested mutations comprise the M252Y mutation, or mutations at Q311, which would strongly suggest to one of ordinary skill in the art that pairing M252Y and Q311 mutations is not favored.”
Applicant’s arguments is not persuasive because IGAWA 2 teaches an Fc region with the exact mutations of present claim 1 as discussed above.
On p. 7, last paragraph, of the reply of 01/14/2026, Applicant argues that “[t]he Office Action cites Davidze for its disclosure of antibodies against alpha-synuclein (a brain antigen), citing page 89, second paragraph and page 140, last paragraph. Page 89, second paragraph contains a bare statement that ‘[i]in some embodiments, the bispecific molecules described herein have a second binding specificity that increases the transport of the molecule into the brain, e.g., across the blood-brain barrier.’ What that binding specificity is, is never described. The page 140 disclosure is a disclosure of brain activity of unmodified antibodies.”
Applicant’s argument is not persuasive because DEVIDZE teaches the treatment of a neurological disorder and expressly states the increased transport of its antibodies into the brain, as Applicant points out. Furthermore, as discussed above, DEVIDZE teaches every mutation of present claims 1 and 5 – 7, and thus, an Fc region having the claimed mutations can be deduced from DEVIDZE’s teachings via routine experimentation. Thus, in view of VISWANATHAN, which teaches an antibody or the Fc conjugate that is active in an in vitro transcytosis assay, wherein the in vitro transcytosis assay comprises cells that express FcRn, it would have been obvious to arrive to the inventions of claims 1, 5 – 7, and 24 – 25 via the teachings of VISWANATHAN in view of DEVIDZE.
Conclusion
Claims 1 – 2, 5 – 7, 12, 16, 24 – 25, 31, and 57 – 59 are rejected.
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/ESTELLA M. GUSTILO/Examiner, Art Unit 1646
/PETER J REDDIG/Primary Examiner, Art Unit 1646