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
RESPONSE TO AMENDMENT
Status of Application/Amendments/claims
2. Applicant’s amendment filed June 20, 2025 is acknowledged. Claims 5-12 and 8-24 are cancelled. Claims 1, 4, 13-14, 25-30 are amended. Claim 32 is newly added. Claims 1-4, 13-17, 25-31 and new claim 32 are pending in this application. Claim 32 is withdrawn without traverse (filed 01/21/2025) from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected non-elected SEQ ID NOs: and non-elected genetic variation, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on January 21, 2025.
3. Claims 1-4, 13-17 and 25-31 are under examination with respect to SEQ ID NOs: 17-18 and 19 for HCDRs1-3, SEQ ID NOs: 4-6 for LCDRs1-3, SEQ ID NOs: 22-23 for VH and VL respectively, neurodegenerative disease for disease and PSEN1 for gene in this office action.
4. Applicant’s arguments filed on June 20, 2025 have been fully considered but they are not deemed to be persuasive for the reasons set forth below.
Priority
5. The priority for the subject matter related to the elected SEQ ID NOs: 22-23 for VH and VL, the elected SEQ ID NOs: 17-18 and 9 and SEQ ID NOs: 4-6 for HCDRs1-3 and LCDRs1-3 respectively in the instant application is May 28, 2020.
Specification
6. The objection to the specification is withdrawn in response to Applicant’s amendment to the specification.
Claim Rejections/Objections Withdrawn
7. The objection to claims 5-10, 14 and 18 is withdrawn in response to Applicant’s amendment to the claims.
The rejection of claims 1-5, 7, 13-17, 22, and 25-31 on the basis that it contains an improper Markush grouping of alternatives is withdraw in response to Applicant’s amendment to the claims and cancelation of claims 5, 7 and 22.
The rejection of claims 5, 7, 22 and 30 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in response to Applicant’s amendment to the claims and cancelation of claims 5, 7 and 22.
The rejection of claims 5, 7 and 22 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, lack of scope of enablement is moot because the claims are canceled.
Claim Rejections/Objections Maintained
In view of the amendment filed on June 20, 2025, the following rejections are maintained.
Claim Rejections - 35 USC § 112
8. 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 1-4, 13-17, 25-29 and 31 stand 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. The rejection is maintained for the reasons of record and the reasons set forth below.
Response to Arguments
On p. 12 of the response, Applicant argues that the rejection has been overcome in view of amendment to claims 1, 4, 14 and 30.
Applicant' s arguments have been fully considered but they are not found persuasive. Contrary to Applicant' s arguments, the examiner asserts that based on MPEP§2171-MPEP§2173, the claims are indefinite because:
i. The term “elevated phosphorylated tau” in claim 1 is a relative term which renders the claim indefinite. The term “elevated phosphorylated tau” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Applicant fails to set forth the metes and bounds of what is encompassed within the definition of “elevated phosphorylated tau”. Since the metes and bounds are unknown, a skilled artisan cannot envision what would be considered as “a disease or condition associated with elevated phosphorylated tau” in a human subject” recited in the claim. Thus the claim is indefinite.
ii. The term "Fc-modified variant” recited in claims 4 and 26 is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Applicant fails to set forth the metes and bounds of what is encompassed within the definition of “Fc-modified variant”. It is unclear what would be modified in the claimed “Fc-modified variant”. Since the metes and bounds are unknown, a skilled artisan cannot envision what would be considered as “an Fc-modified variant” recited in the claims. Thus, the claims are indefinite.
iii. The rest of the claims are indefinite as depending from an indefinite claim.
Accordingly, the rejection of claims 1-4, 13-17, 25-29 and 31 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is maintained.
Claim Rejections - 35 USC § 112
9. 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 1-4, 13-17 and 25-31 stand rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for reducing levels of paired helical filaments of phosphorylated (PHF)-tau induced by intravitreally injection of human APOE3 into a retina of an eye in an intraocular model of inducible APOE-dependent hyperphosphorylation, a B6;C3-Tg(Pmp-MAPT*P301S)PS19Vle/J mouse, by intravitreally administering 1H4-2 antibody or humanized 1343Ah antibody into the eye of the mouse compared to a wild type control mouse, does not reasonably provide enablement for a method for treating all forms of undefined diseases or conditions associated with elevated phosphorylated Tau or all forms of neurodegenerative diseases or diseases recited in claims 15-16 using the claimed antibody comprising a VH and a VL having recited SEQ ID NOs: for HCDRs1-3 and LCDRs1-3 or VH and VL or inhibiting or preventing binding of a HSPG to ApoE by contacting a structurally and functionally undefined polypeptide with an structurally and functionally undefined anti-ApoE domain to ApoE comprising the amino acid sequence set forth in SEQ ID NO:3, and wherein the anti-ApoE domain competes with or binds a same epitope as a reference antibody having a VH of SEQ ID NO:22 and a VL of SEQ ID NO:23 as broadly claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. The rejection is maintained for the reasons of record and the reasons set forth below.
Claims 1-4, 13-17, 25-29 and 31 as amended are drawn to a method of treating a disease or condition associated elevated phosphorylated Tau in a human subject in need thereof, comprising administering to the human subject a therapeutically effective amount an antibody or antigen-binding portion thereof, wherein the antibody or antigen-binding portion thereof comprises a VH comprising HCDRs1-3 according to recited SEQ ID NOs: 17-18 and 9 respectively and a VL comprising LCDRs1-3 according to recited SEQ ID NOs: 4-6 respectively or an antibody or antigen-binding portion thereof comprising a VH with at least 80%, 90% or 95% sequence identity to aa 20-139 of SEQ ID NO:22 and VHCDR1-3 of SEQ ID NOs: 17-18 and 9 respectively, and a VL with at least 80%, 90% or 95%sequence identity to aa 21-131 of SEQ ID NO:23 and VLCDR1-3 of SEQ ID NOs: 4-6 respectively.
Claim 30 as amended is drawn to a method of inhibiting or preventing binding of a HSPG or heparin to ApoE, comprising contacting a polypeptide with an anti-ApoE domain to ApoE comprising the amino acid sequence set forth in SEQ ID NO:3, and wherein the anti-ApoE domain competes with or binds a same epitope as a reference antibody having a VH of SEQ ID NO:22 and a VL of SEQ ID NO:23.
Response to Arguments
On p. 13-15 of the response, Applicant argues that: i) the rejection has been overcome in view of amendment to claim 1 by specifying that the disease or condition is associated with elevated phosphorylated Tau; ii) the specification provides support for instant claims in Examples 8-9 by showing antibody 7C11 was capable of reducing binding between ApoE3 to heparin as in claim 30 and that the antibody 1H4-2 was capable of reducing levels of phosphorylated Tau; iii) interaction between ApoE and HSPG is involved in pathogenesis of certain neurodegenerative diseases such as Alzheimer’s disease (see p. 12-14), and antibody 7C11 was capable of reducing binding between ApoE3 to heparin.
Applicant's arguments have been fully considered but they are not found persuasive. Contrary to Applicant's arguments, the examiner asserts that based on MPEP §2164, MPEP §§2164.01-2164.06(b) & 2164.08, the specification provides insufficient guidance to enable a skilled artisan to practice the full scope of the claimed invention without undue experimentation because:
i. The claims 1-5, 7, 13-17, 22, 25-29 and 31 encompass a method of using antibodies comprising a VH and a VL having recited SEQ ID NOs: for HCDRs1-3 and LCDRs1-3 for treating undefined diseases associated with elevated phosphorylated Tau including all forms of neurodegenerative diseases and all forms of AD and other diseases recited in claims 15-16.
The claim 30 encompasses a method of using a structurally and functionally undefined polypeptide and a structurally and functionally undefined anti-ApoE domain that competes with or binds a same epitope as a reference antibody having a VH of SEQ ID NO:22 and a VL of SEQ ID NO:23 for inhibiting and preventing binding a HSPG or heparin to ApoE in vitro or in vivo.
ii. The specification provides no well-established structural and functional relationship or correlation between the claimed anti-ApoE antibody comprising SEQ ID NOs: 17-18 and 9 for HCDR1-3 respectively and SEQ ID NOs: 4-6 for LCDR1-3 respectively and antibody 1H4-2 (which comprises different sequences for HCDR1-2) because the sequences of HCDR1-2 of antibody 1H4-2 are different from those of antibody 7C11-1 (see the sequence alignment below).
The specification only describes reducing levels of human APOE3-induced PHF-tau in a retina of an eye of an intraocular model of inducible APOE-dependent hyperphosphorylation (i.e. a B6;C3-Tg(Pmp-MAPT*P301S)PS19Vle/J mouse) compared to a wild type control mouse by intravitreally administering 1H4-2 antibody or humanized 1343Ah antibody into the eye of the mouse.
The 1H4-2 antibody was raised against KLH-CTEELRVRLASHLRK-CONH2 (SEQ ID NO:54) and has the amino acid sequences for LCDRs, HCDRs1-3, VL, VH, LC and HC as listed below. However, the claimed antibody recited instant claims have different sequences for HCDR1-2 (SEQ ID NOs: 17-18) from the sequences of HCDR1-2 of the 1H4-2 antibody (see the sequence alignment below).
The specification fails to teach what specific structures/amino acid sequences are required by the claimed antibodies comprising different SEQ ID NOs: for HCDRs1-3 and LCDRs1-3. The specification also fails to teach what other structures/amino acid sequences can or cannot not be included/changed in other antibody variants with 80% identity to the claimed SEQ ID NOs: 23 and 22 for VH and VL in order to preserve the activity of the 1H4-2 antibody or humanized 1343Ah antibody in reducing human APOE3-induced PHF-tau in a retina of an eye of an intraocular model of inducible APOE-dependent hyperphosphorylation (i.e. a B6;C3-Tg(Pmp-MAPT*P301S)PS19Vle/J mouse) compared to a wild type control mouse or even in treating all forms of diseases or all forms of neurodegenerative diseases including all forms of AD, indicating that undue experimentation is required by a skilled artisan to perform while practicing the claimed invention.
Antibodies Raised Against SEQ ID NO:54
SEQ ID NO:
Antibody LC VL LCDR1 LCDR2 LCDR3 HC VH HCDR1 HCDR2 HCDR3
1H4-2 12 4 5 6 13 7 8 9
7C11-1 23 14 15 16 22 17 18 19
*Note that the sequences of SEQ ID NOs:4-6 are identical to those of SEQ ID NOs: 14-16 respectively.
**Note that the sequence of SEQ ID NO:9 is identical to that of SEQ ID NO:19.
***But the sequences of SEQ ID NOs:7-8 are different from those of SEQ ID NOs: 17-18.
VH
SEQ ID NO:22(VH) 1 MNFGLSVIFLVLVLKGVLCEVKLVESGGGLVQPGGSLKLSCAASGFTFSRYTMSWVRQTP 60
SEQ ID NO:13(VH) 1 MNFGLSLIFLVLVLKGVLCEVKLVESGGGVVQPGGSLKLSCAASGFTFSSYTMSWVRQTP 60
SEQ ID NO:7(HCDR1) -------------------------------------------------SYTMS------
SEQ ID NO:17(HCDR1) 1 -------------------------------------------------RYTMS------ 5
SEQ ID NO:8(HCDR2) ------------------------------------------------------------
SEQ ID NO:18(HCDR2) ------------------------------------------------------------
SEQ ID NO:9(HCDR3) ------------------------------------------------------------
SEQ ID NO:19(HCDR3) ------------------------------------------------------------
SEQ ID NO:22(VH) 61 EKRLEWVAKIRNVGGITYYPDTVKGRFTISRDNAKNTLYLQMSSLKSEDTAMYYCARHYY 120
SEQ ID NO:13(VH) 61 EKRLEWVAKIRNGGGITYYLDTLKGRFTISRDNAKNTLYLQMSSLKSEDTAIYFCARHYY 120
SEQ ID NO:7(HCDR1) ------------------------------------------------------------
SEQ ID NO:17(HCDR1) ------------------------------------------------------------
SEQ ID NO:8(HCDR2) 1 --------KIRNGGGITYYLDTLKG----------------------------------- 17
SEQ ID NO:18(HCDR2) 1 --------KIRNVGGITYYPDTVKG----------------------------------- 17
SEQ ID NO:9(HCDR3) 1 ---------------------------------------------------------HYY 3
SEQ ID NO:19(HCDR3) 1 ---------------------------------------------------------HYY 3
SEQ ID NO:22(VH) 121 GSEDYFDYWGQGTTLTVSS 139
SEQ ID NO:13(VH) 121 GSEDYFDYWGQGTTLTVSS 139
SEQ ID NO:7(HCDR1) -------------------
SEQ ID NO:17(HCDR1) -------------------
SEQ ID NO:8(HCDR2) -------------------
SEQ ID NO:18(HCDR2) -------------------
SEQ ID NO:9(HCDR3) 4 GSEDYFDY----------- 11
SEQ ID NO:19(HCDR3) 4 GSEDYFDY----------- 11
*Note that Only the sequence of SEQ ID NO:9 is IDENTICAL to that of SEQ ID NO:19
**But the sequences of SEQ ID NOs:7-8 are DIFFERENT from those of SEQ ID NOs: 17-18.
iii. There is no well-established structural and functional relationship or correlation between the claimed polypeptide with an anti-ApoE domain that competes with or binds a same epitope as a reference antibody having a VH of SEQ ID NO:22 and a VL of SEQ ID NO:23 recited in claim 30 and the antibody 7C11-1 shown in Example 8 in inhibiting and preventing binding a HSPG or heparin to ApoE in vitro or even in vivo.
The specification fails to teach what the claimed polypeptide with an anti-ApoE domain is. The specification fails to teach what specific common sequences, structures and characteristics are required by the claimed polypeptide with an anti-ApoE domain possessing a property of competing with a reference antibody having the recited SEQ ID NOs: for VH and VL. The specification fails to teach what structures/amino acid sequences can or cannot not be included/changed in the claimed structurally and functionally undefined polypeptides and anti-ApoE domain in order to preserve the activity of the 7C11-1 antibody in inhibiting and preventing binding a HSPG or heparin to ApoE in vitro shown in Example 8 (p. 108-109, Figure 23A-B). A skilled artisan cannot contemplate how to make and use the claimed polypeptide in inhibiting and preventing binding a HSPG or heparin to ApoE in vitro or even in vivo, indicating that undue experimentation is required by a skilled artisan to perform while practicing the claimed invention.
iv. There is no well-established correlation between all forms of undefined diseases associated with elevated phosphorylated Tau including all forms of neurodegenerative diseases and all forms of AD and other diseases recited in claims 15-16 caused by all possible mechanisms and an intraocular model of inducible APOE-dependent hyperphosphorylation, a B6;C3-Tg(Pmp-MAPT*P301S)PS19Vle/J mouse used in Example 9).
There is no well-established structural and functional relationship or correlation between treatment of all forms of undefined diseases associated with elevated phosphorylated Tau including all forms of neurodegenerative diseases and all forms of AD and other diseases recited in claims 15-16 by the claimed anti-ApoE antibody and reducing human ApoE3-induced levels of paired helical filaments of phosphorylated (PHF)-tau in an intraocular model of inducible APOE-dependent hyperphosphorylation, B6;C3-Tg(Pmp-MAPT*P301S)PS19Vle/J mice by intravitreal injection of 1H4-2 antibody or humanized 1343Ah antibody into an eye of the intraocular model.
The specification fails to provide sufficient guidance or evidence to demonstrate that all forms of diseases or conditions associated with elevated phosphorylated Tau including all forms of neurodegenerative diseases and all forms of AD caused by all possible mechanisms can be treated by the claimed antibody because there is no well-established correlation between reduction of human APOE3-induced PHF-tau in a retina of an eye of an intraocular model of inducible APOE-dependent hyperphosphorylation (i.e. a B6;C3-Tg(Pmp-MAPT*P301S)PS19Vle/J mouse) compared to a wild type control mouse by the 1H4-2 antibody or humanized 1343Ah antibody and the pathogeneses or causes of all forms of diseases or conditions associated with elevated phosphorylated Tau including all forms of neurodegenerative diseases and all forms of AD caused by all possible mechanisms.
As previously made of record, the molecular mechanisms underlying all forms of diseases associated with elevated phosphorylate Tau or all forms of neurodegenerative diseases including AD are unclear or unknown. For example, the molecular mechanisms underlying cognitive dysfunction or dementia of AD are unclear (see p. 94; Henstridge et al. Nat. Rev. Neurosci. 2019; 20: 94-107). The specification provides insufficient guidance to demonstrate that administration of the claimed antibody comprising recited SEQ ID NOs: for HCDRs1-3 and LCDRs1-3 can treat cognitive dysfunction or dementia in AD because elevated Abeta accumulation and/or hyperphosphorylated tau is not the only cause of cognitive dysfunction or dementia in AD. Several factors and genes are involved in pathogenesis of AD including ageing, inflammation and immune response, APP, presenilin1/2, ApoE and genes involved in the amyloid cascade, genes involved in the mitochondrial cascade (see p. 348-344, Swerdlow, Clin. Interv. Ageing 2007; 2:347-359; p. abstract; Atwood et al., J. Alzheimer’s Disease; 2015; 47:33-47; p. 95-103; Henstridge et al., Nat. Rev. Neurosci. 2019; 20: 94-107, cited previously). In addition, fully developed animal models for neurodegenerative diseases are still lacking especially for AD because the complexity of the disease and deficiency of characterized cognition (see p. 403, abstract. Anger. Neurotoxicology 1991. 12: 403-13, cited previously). For example, an animal model of brain amyloidosis induced by acute or infusion of A can only be used for screening for inhibiting the formation of A but not for evaluating the generation of A by the effects of -and -secretase, which is another molecular mechanism for the pathogenesis of AD (see p. 106, 1st col, 2nd paragraph, Tayebati. Mech. Ageing Dev. 2006. 127: 100-8, cited previously). In the instant case, the intraocular model of inducible APOE-dependent hyperphosphorylation (i.e. a B6;C3-Tg(Pmp-MAPT*P301S)PS19Vle/J mouse) as described in the instant specification can only be used for evaluating the effects of an antibody on reducing levels of human APOE3-induced PHF-tau in a retina of an eye of an intraocular model of inducible APOE-dependent hyperphosphorylation based on a human tau P301S mutation, i.e. B6;C3-Tg(Pmp-MAPT*P301S)PS19Vle/J mice.
Each type of animal models of diseases associated with elevated phosphorylated Tau, or neurodegenerative diseases or each type of animal models of AD only reflects part of pathogenesis of the disease as taught by Tayebati (see p. 106, 1st col, 2nd paragraph, Tayebati, Mech. Ageing Dev. 2006. 127: 100-8, cited previously) and Sarter (see p. 645, abstract, Sarter, Neurosci. and Biobehav. Rev. 2004. 28: 645-650, cited previously). Applicant obviously intended to treat all forms of diseases associated with elevated phosphorylated tau, and all forms of neurodegenerative diseases including all forms of AD by using the claimed antibody comprising recited SEQ ID NOs: for HCDRs1-3 and LCDRs1-3. Applicant also obviously intended to inhibit or prevent binding a HSPG or heparin to ApoE in vivo in all forms of diseases and conditions associated elevated phosphorylated Tau using the claimed antibody or a structurally and functionally undefined polypeptide with a structurally and functionally undefined anti-ApoE domain. However, the specification fails to provide a well-established correlation among different forms of undefined diseases associated with elevated phosphorylated Tau, different forms of neurodegenerative diseases and different forms of AD caused by different mechanisms. The specification fails to establish that different forms of undefined diseases associated with elevated phosphorylated Tau, different forms of neurodegenerative diseases and different forms of AD caused by all possible mechanisms can be treated by the same drugs or same conditions or have the same effects in response to the same drugs.
Since the pathogenesis of AD or other undefined diseases associated with elevated phosphorylated tau and neurodegenerative diseases is complex and the causes of dementia/cognitive dysfunction in AD have not been deciphered and are equally complex, it is unpredictable whether the reduction of human APOE3-induced PHF-tau in a retina of an eye of an intraocular model of inducible APOE-dependent hyperphosphorylation (i.e. a B6;C3-Tg(Pmp-MAPT*P301S)PS19Vle/J mouse) compared to a wild type control mouse by the 1H4-2 antibody or humanized 1343Ah antibody can be applied to other forms of AD caused by other mechanisms or other undefined diseases and neurodegenerative diseases associated with elevated phosphorylated Tau, or whether administration of the claimed antibody comprising recited SEQ ID NOs: for HCDRs1-3 and LCDRs1-3 or the claimed structurally and functionally undefined polypeptide with a structurally and functionally undefined anti-ApoE domain can treat all forms of AD or all forms of diseases associated with elevated phosphorylated tau including neurodegenerative diseases and other diseases recited in claims 15-16. Thus, a skilled artisan cannot contemplate how to make and use the claimed invention, indicating that undue experimentation is required by a skilled artisan to perform while practicing the claimed invention.
Therefore, in view of the breadth of the claims, the lack of guidance in the specification, the limited examples, the unpredictability of inventions, and the current status of the art, undue experimentation would be required by one of skill in the art to perform in order to practice the full scope of the claimed invention as it pertains to a method for treating a disease associated with elevated phosphorylated Tau by the claimed antibody or a method of inhibiting and preventing binding a HSPG or heparin to ApoE in vitro or in vivo in all forms of diseases and conditions by contacting a polypeptide with an anti-ApoE domain to an ApoE comprising the amino acid sequence set forth in SEQ ID NO:3 and wherein the anti-ApoE domain can compete with a reference antibody having recited SEQ ID NOs:.
Accordingly, the rejection of claims 1-4, 13-17 and 25-31 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, lack of scope of enablement is maintained.
Claim Rejections - 35 USC § 112
10 Claims 1-4, 13-17 and 25-31 stand 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. The rejection is maintained for the reasons of record and the reasons set forth below.
Claims 1-4, 13-17, 25-29 and 31 as amended encompass using an anti-ApoE antibody comprising a VH having HCDRs1-3 of SEQ ID NOs: 17-18 and 9 respectively and a VL having LCDRs1-3 of SEQ ID NOs: 4-6 respectively for treating a genus of diseases associated with elevated phosphorylated tau, and including a genus of neurodegenerative diseases recited in claims 15-16.
Claim 14 encompasses using a genus of the anti-ApoE antibody comprising recited SEQ ID NOs: for HCDRs1-3 and LCDRs1-3 and wherein the anti-ApoE antibody has the properties of binding to ApoE3 of SEQ ID NO:3 with a KD of 20nM or less; Kon of 3x105l/Ms or more; or Koff of about 1x10-4 1/s or less
Claims 4 and 26 encompass using a genus of Fc-modified variant.
Claim 30 encompasses using a genus of structurally and functionally undefined polypeptide and a genus of structurally and functionally undefined anti-ApoE domain for inhibiting and preventing binding a HSPG or heparin to ApoE in vitro or in vivo in all possible conditions.
Response to Arguments
On p. 15-16 of the response, Applicant argues that the rejection has been overcome in view of amendment to claim 1 by reciting specific SEQ ID NOs: for HCDR1-3 and LCDR1-3 and the specification provides support at p. 20-22 and Example 8.
Applicant's arguments have been fully considered but they are not found persuasive. Contrary to Applicant's arguments, the examiner asserts that based on MPEP §2163, MPEP §§2163.01-2163.03, the specification fails to provide sufficient description or information or evidence to demonstrate that Applicant is in possession of treating the claimed genus of diseases or disorders associated with elevated phosphorylated Tau in a human subject in need thereof using the claimed antibody because:
i. The specification provides no well-established structural and functional relationship or correlation between the claimed anti-ApoE antibody comprising SEQ ID NOs: 17-18 and 9 for HCDR1-3 respectively and SEQ ID NOs: 4-6 for LCDR1-3 respectively and antibody 1H4-2 (which comprises different sequences for HCDR1-2) because the sequences of HCDR1-2 of antibody 1H4-2 are different from those of antibody 7C11-1 (see the sequence alignment below).
The specification only describes reducing levels of human APOE3-induced PHF-tau in a retina of an eye of an intraocular model of inducible APOE-dependent hyperphosphorylation (i.e. a B6;C3-Tg(Pmp-MAPT*P301S)PS19Vle/J mouse) compared to a wild type control mouse by intravitreally administering 1H4-2 antibody or humanized 1343Ah antibody into the eye of the mouse. The 1H4-2 antibody was raised against KLH-CTEELRVRLASHLRK-CONH2 (SEQ ID NO:54), have the amino acid sequences for LCDRs, HCDRs1-3, VL, VH, LC and HC as listed below.
Antibodies Raised Against SEQ ID NO:54
SEQ ID NO:
Antibody LC VL LCDR1 LCDR2 LCDR3 HC VH HCDR1 HCDR2 HCDR3
1H4-2 12 4 5 6 13 7 8 9
However, the claimed antibody recited instant claims have different sequences for HCDR1-2 (SEQ ID NOs: 17-18) from the sequences of HCDR1-2 of the 1H4-2 antibody. The specification fails to teach what specific structures/amino acid sequences are required by the claimed antibodies comprising different SEQ ID NOs: for HCDRs1-3 and LCDRs1-3 in order to preserve the activity of the 1H4-2 antibody in reducing human APOE3-induced PHF-tau in a retina of an eye of an intraocular model of inducible APOE-dependent hyperphosphorylation (i.e. a B6;C3-Tg(Pmp-MAPT*P301S)PS19Vle/J mouse) compared to a wild type control mouse. The specification also fails to teach what other structures/amino acid sequences can or cannot not be included/changed in other antibody variants with 80% identity to the claimed SEQ ID NOs: 23 and 22 for VH and VL in order to preserve the activity of the 1H4-2 antibody in reducing human APOE3-induced PHF-tau in a retina of an eye of an intraocular model of inducible APOE-dependent hyperphosphorylation (i.e. a B6;C3-Tg(Pmp-MAPT*P301S)PS19Vle/J mouse) compared to a wild type control mouse or even in treating all forms of diseases associated with elevated phosphorylated Tau and all forms of neurodegenerative diseases including all forms of AD caused by all possible mechanisms. Since the common characteristics/features of other anti-ApoE antibody variants are unknown, a skilled artisan cannot envision the functional correlations of the claimed genus of anti-ApoE antibody variants with the claimed invention.
ii. There is no well-established structural and functional relationship or correlation between the claimed polypeptide with an anti-ApoE domain that competes with or binds a same epitope as a reference antibody having a VH of SEQ ID NO:22 and a VL of SEQ ID NO:23 recited in claim 30 and the antibody 7C11-1 shown in Example 8 in inhibiting and preventing binding a HSPG or heparin to ApoE in vitro or even in vivo.
The specification fails to teach what the claimed polypeptide with an anti-ApoE domain is. The specification fails to teach what specific common sequences, structures and characteristics are required by the claimed polypeptide with an anti-ApoE domain possessing a property of competing with a reference antibody having the recited SEQ ID NOs: for VH and VL. The specification fails to teach what structures/amino acid sequences can or cannot not be included/changed in the claimed structurally and functionally undefined polypeptides and anti-ApoE domain in order to preserve the activity of the 7C11-1 antibody in inhibiting and preventing binding a HSPG or heparin to ApoE in vitro shown in Example 8 (p. 108-109, Figure 23A-B). Since the common characteristics/features of the claimed genus of structurally and functionally undefined polypeptides are unknown, a skilled artisan cannot envision the functional correlation of the claimed genus of polypeptide with the claimed invention.
iii. There is no well-established correlation between all forms of undefined diseases associated with elevated phosphorylated Tau including all forms of neurodegenerative diseases and all forms of AD and other diseases recited in claims 15-16 caused by all possible mechanisms and an intraocular model of inducible APOE-dependent hyperphosphorylation, a B6;C3-Tg(Pmp-MAPT*P301S)PS19Vle/J mouse used in Example 9).
There is no well-established structural and functional relationship or correlation between treatment of all forms of undefined diseases associated with elevated phosphorylated Tau including all forms of neurodegenerative diseases and all forms of AD and other diseases recited in claims 15-16 by the claimed anti-ApoE antibody and reducing human ApoE3-induced levels of paired helical filaments of phosphorylated (PHF)-tau in an intraocular model of inducible APOE-dependent hyperphosphorylation, B6;C3-Tg(Pmp-MAPT*P301S)PS19Vle/J mice by intravitreal injection of 1H4-2 antibody or humanized 1343Ah antibody into an eye of the intraocular model.
Since the common characteristics/features of other anti-ApoE antibody variants, or the claimed genus of structurally and functionally undefined polypeptides and the claimed genus of structurally and functionally undefined anti-ApoE domains and the claimed genus of Fc-modified variants are unknown, a skilled artisan cannot envision the functional correlations of the genus with the claimed invention.
Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of using the genus of anti-ApoE antibody variants, the genus of polypeptides, the genus of anti-ApoE domain or the genus of Fc-modified variants for treating the genus of diseases associated with elevated phosphorylated Tau.
Based on MPEP § 2161.01 and §2163, “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. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116”.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
As discussed above, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus of anti-ApoE antibody variants, the genus of polypeptides, the genus of anti-ApoE domain or the genus of Fc-modified variants in treating the genus of diseases associated with elevated phosphorylated Tau, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483 and Centocor v. Abbott, 636 F.3d1341 (Fed. Cir. 2011) and AbbVie v. Janssen, 759 F.3d 1285 (Fed. Cir.2014). One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483.
Therefore, the claimed methods have not met the written description provision of 35 U.S.C. §112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115). Applicant is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, ¶ 1 "Written Description" Requirement. See MPEP § 2161.01 and 2163.
Accordingly, the rejection of claims 1-4, 13-17 and 25-31 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 maintained.
Conclusion
11. NO CLAIM IS ALLOWED.
Sequence alignment
epitope
SEQ ID NO:57 1 ---------------STEELRVRLASHLRKLRKRLLRDADDLQK 29
SEQ ID NO:59 1 RLVQYRGEVQAMLGQSTEELRVRLASHLRKL------------- 31
SEQ ID NO:3 1 ----------------TEELRVRLASHLRK-------------- 14
SEQ ID NO:54 1 ---------------CTEELRVRLASHLRK-------------- 15
SEQ ID NO:58 1 ---------------STEELRVSLASHLRKLRKRLLRDADDLQK 29
SEQ ID NO:60 1 RLVQYRGEVQAMLGQSTEELRVSLASHLRKL------------- 31
SEQ ID NO:2 1 ----------------TEELRVSLASHLRK-------------- 14
SEQ ID NO:55 1 ---------------CTEELRVSLASHLRK-------------- 15
VH
SEQ ID NO:22(VH) 1 MNFGLSVIFLVLVLKGVLCEVKLVESGGGLVQPGGSLKLSCAASGFTFSRYTMSWVRQTP 60
SEQ ID NO:13(VH) 1 MNFGLSLIFLVLVLKGVLCEVKLVESGGGVVQPGGSLKLSCAASGFTFSSYTMSWVRQTP 60
SEQ ID NO:43(VH) 1 MKCSWVIFFLMAVVTGVNSEVQLQQSGAELVRPGALVKWSCKASGFNIKDYHIHWVKQRP 60
SEQ ID NO:33(VH) 1 MKCSWVIFFLMAVVTGVNSEVQLQQSGAELVRPGALVKLSCKASGFNIKDYHMHWVKERP 60
SEQ ID NO:7(HCDR1) -------------------------------------------------SYTMS------
SEQ ID NO:17(HCDR1) 1 -------------------------------------------------RYTMS------ 5
SEQ ID NO:8(HCDR2) ------------------------------------------------------------
SEQ ID NO:18(HCDR2) ------------------------------------------------------------
SEQ ID NO:9(HCDR3) ------------------------------------------------------------
SEQ ID NO:19(HCDR3) ------------------------------------------------------------
SEQ ID NO:22(VH) 61 EKRLEWVAKIRNVGGITYYPDTVKGRFTISRDNAKNTLYLQMSSLKSEDTAMYYCARHYY 120
SEQ ID NO:13(VH) 61 EKRLEWVAKIRNGGGITYYLDTLKGRFTISRDNAKNTLYLQMSSLKSEDTAIYFCARHYY 120
SEQ ID NO:43(VH) 61 EQGLDWIGWIDPEIDKTLYDPKFQGKARITADTSSNTAYLQLSSLTSEDTAVYYCARGTA 120
SEQ ID NO:33(VH) 61 EQGLEWIGWIDPENGNTMYDPKFQGKASITADTSSNTAYLQLSSLTSEDTAVYYCVRGTA 120
SEQ ID NO:7(HCDR1) ------------------------------------------------------------
SEQ ID NO:17(HCDR1) ------------------------------------------------------------
SEQ ID NO:8(HCDR2) 1 --------KIRNGGGITYYLDTLKG----------------------------------- 17
SEQ ID NO:18(HCDR2) 1 --------KIRNVGGITYYPDTVKG----------------------------------- 17
SEQ ID NO:9(HCDR3) 1 ---------------------------------------------------------HYY 3
SEQ ID NO:19(HCDR3) 1 ---------------------------------------------------------HYY 3
SEQ ID NO:22(VH) 121 GSEDYFDYWGQGTTLTVSS 139
SEQ ID NO:13(VH) 121 GSEDYFDYWGQGTTLTVSS 139
SEQ ID NO:43(VH) 121 RAS--FDYWGQGTTLTVSS 137
SEQ ID NO:33(VH) 121 RAS--FDYWGQGTTLTVSS 137
SEQ ID NO:7(HCDR1) -------------------
SEQ ID NO:17(HCDR1) -------------------
SEQ ID NO:8(HCDR2) -------------------
SEQ ID NO:18(HCDR2) -------------------
SEQ ID NO:9(HCDR3) 4 GSEDYFDY----------- 11
SEQ ID NO:19(HCDR3) 4 GSEDYFDY----------- 11
*Note that Only the sequence of SEQ ID NO:9 is IDENTICAL to that of SEQ ID NO:19
**But the sequences of SEQ ID NOs:7-8 are DIFFERENT from those of SEQ ID NOs: 17-18.
VL
SEQ ID NO:23(VL) 1 METDTILLWVLLLWVPGSTGDNVLTQSPASLAVSLGQRATISCKASQSVDYDGDSYMNWY 60
SEQ ID NO:12(VL) 1 METDTILLWVLLLWVPGSTGDNVLTQSPASLAVSLGQRATISCKASQSVDYDGDSYMNWY 60
SEQ ID NO:42(VL) 1 METDTILLWVLLLWVPGSTGDIVLTQSPASLAVSLGQRATISCKASQSVDYDGDTYMNWY 60
SEQ ID NO:32(VL) 1 METDTILLWVLLLWVPGSTGDIVLTQSPASLAVSLGQRATISCKASQSVDYDGDSYMNWY 60
SEQ ID NO:4(LCDR1) 1 -------------------------------------------KASQSVDYDGDSYMN-- 15
SEQ ID NO:14(LCDR1) 1 -------------------------------------------KASQSVDYDGDSYMN-- 15
SEQ ID NO:34(LCDR1) 1 -------------------------------------------KASQSVDYDGDTYMN-- 15
SEQ ID NO:44(LCDR1) 1 -------------------------------------------KASQSVDYDGENYMN-- 15
SEQ ID NO:5(LCDR2) ------------------------------------------------------------
SEQ ID NO:15(LCDR2) ------------------------------------------------------------
SEQ ID NO:35(LCDR2) ------------------------------------------------------------
SEQ ID NO:45(LCDR2) ------------------------------------------------------------
SEQ ID NO:6(LCDR3) ------------------------------------------------------------
SEQ ID NO:16(LCDR3) ------------------------------------------------------------
SEQ ID NO:26(LCDR3) ------------------------------------------------------------
SEQ ID NO:46(LCDR3) ------------------------------------------------------------
SEQ ID NO:23(VL) 61 QQKPGQPPKVFIYAASNLESGIPARFSGSGSGTNFTLNIHPVEEEDAATYYCQQSNEDPW 120
SEQ ID NO:12(VL) 61 QQKPGQPPKVFIYAASNLESGIPARFSGSGSGTDFTLNIHPVEEEDAATYYCQQSNEDPW 120
SEQ ID NO:42(VL) 61 QQKPGQPPKLLIYTASNLESGIPARFSGSGSGTDFTLNIHPVEEVDAATYYCQQSNEDPW 120
SEQ ID NO:32(VL) 61 QQKSGQPPKLLIYAASNLESGIPARFSGSGSGTDFTLNIHPVEEEDAATYYCQQSNVDPW 120
SEQ ID NO:4(LCDR1) ------------------------------------------------------------
SEQ ID NO:14(LCDR1) ------------------------------------------------------------
SEQ ID NO:34(LCDR1) ------------------------------------------------------------
SEQ ID NO:44(LCDR1) ------------------------------------------------------------
SEQ ID NO:5(LCDR2) 1 -------------AASNLES---------------------------------------- 7
SEQ ID NO:15(LCDR2) 1 -------------AASNLES---------------------------------------- 7
SEQ ID NO:35(LCDR2) 1 -------------TASNLES---------------------------------------- 7
SEQ ID NO:45(LCDR2) 1 -------------VASNLES---------------------------------------- 7
SEQ ID NO:6(LCDR3) 1 ----------------------------------------------------QQSNEDPW 8
SEQ ID NO:16(LCDR3) 1 ----------------------------------------------------QQSNEDPW 8
SEQ ID NO:26(LCDR3) 1 ----------------------------------------------------QQSNVDPW 8
SEQ ID NO:46(LCDR3) 1 ----------------------------------------------------QQSNLDPW 8
SEQ ID NO:23(VL) 121 TFGGGTKLEIK 131
SEQ ID NO:12(VL) 121 TFGGGTKLEIK 131
SEQ ID NO:42(VL) 121 TFGGGTKLEIK 131
SEQ ID NO:32(VL) 121 TFGGGTKLEIK 131
SEQ ID NO:4(LCDR1) -----------
SEQ ID NO:14(LCDR1) -----------
SEQ ID NO:34(LCDR1) -----------
SEQ ID NO:44(LCDR1) -----------
SEQ ID NO:5(LCDR2) -----------
SEQ ID NO:15(LCDR2) -----------
SEQ ID NO:35(LCDR2) -----------
SEQ ID NO:45(LCDR2) -----------
SEQ ID NO:6(LCDR3) 9 T---------- 9
SEQ ID NO:16(LCDR3) 9 T---------- 9
SEQ ID NO:26(LCDR3) 9 T---------- 9
SEQ ID NO:46(LCDR3) 9 T---------- 9
*Note that the sequences of SEQ ID NOs:4-6 are IDENTICAL to those of SEQ ID NOs: 14-16.
**But the sequences of SEQ ID NOs:4-6/14-16 are DIFFERENT from those of SEQ ID NOs: 34-35 and 16 or SEQ ID NOs:44-46.
LCDRs1-3/VL=31/131=23.6%
VL: 131 aa
LCDRs1-3: 15+7+9=31aa
HCDRs1-3/VH=33/139=23.7%
VH: 139 aa
HCDRs1-3: 5+17+11=33aa
12. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
WO2012075422 teaches an anti-ApoE antibody comprising a light chain that is 87.% identical to instant SEQ ID NO:52 (see the sequence alignment below).
SEQ ID NO:52
AZX12838
ID AZX12838 standard; protein; 229 AA.
XX
AC AZX12838;
XX
DT 02-AUG-2012 (first entry)
XX
DE Anti-apolipoprotein E monoclonal antibody (mAb) light chain, SEQ ID 3.
XX
KW APOE; Apolipoprotein E; antibody therapy; light chain;
KW monoclonal antibody; therapeutic.
XX
OS Mus musculus.
XX
FH Key Location/Qualifiers
FT Region 44..58
FT /label= Complementarity_determining_region_1
FT Region 74..80
FT /label= Complementarity_determining_region_2
FT Region 113..121
FT /label= Complementarity_determining_region_3
XX
CC PN WO2012075422-A2.
XX
CC PD 07-JUN-2012.
XX
CC PF 02-DEC-2011; 2011WO-US063121.
XX
PR 02-DEC-2010; 2010US-0419060P.
PR 18-OCT-2011; 2011US-0548542P.
XX
CC PA (UNIW ) UNIV WASHINGTON.
XX
CC PI Holtzman D, Kim J, Jiang H;
XX
DR WPI; 2012-G33354/41.
DR N-PSDB; AZX12836.
XX
CC PT New isolated antibody that specifically binds apolipoprotein E (ApoE),
CC PT useful for treating at least one symptom or sign of amyloid beta plaque
CC PT associated symptoms in subject, and for decreasing amyloid plaque load in
CC PT brain of subject.
XX
CC PS Claim 3; SEQ ID NO 3; 41pp; English.
XX
CC The present invention relates to a novel isolated anti-apolipoprotein E
CC (ApoE) antibody derived from a hybridoma selected from HJ6.1 (ATCC Patent
CC Deposit Designation PT-11805), HJ6.2 (ATCC Patent Deposit Designation PT-
CC 11806), HJ6.3 (ATCC Patent Deposit Designation PT-11807), and HJ6.4 (ATCC
CC Patent Deposit Designation PT-11808). The invention also provides: a
CC method for treating at least one symptom or sign of amyloid beta plaque
CC associated symptoms in a subject by administering an effective amount of
CC anti-ApoE antibody to the subject; and a method for decreasing amyloid
CC plaque load in brain of a subject. The present sequence represents an
CC anti-apolipoprotein E monoclonal antibody (mAb) antibody light chain,
CC which may be used in the preparation of antibody used in the invention.
CC Note: The present sequence is described as a DNA sequence in claim 3 but
CC is shown as an amino acid sequence in the sequence listing.
XX
SQ Sequence 229 AA;
Query Match 87.0%; Score 1005; Length 229;
Best Local Similarity 90.4%;
Matches 189; Conservative 9; Mismatches 11; Indels 0; Gaps 0;
Qy 1 DIVLTQSPASLAVSLGQRATISCKASQSVDYDGENYMNWYQQKPGQSPKLLIYVASNLES 60
|||||||||||||||||||||||:||:||:| | : | |||||||| |||||| |||:||
Db 21 DIVLTQSPASLAVSLGQRATISCRASESVEYYGTSLMQWYQQKPGQPPKLLIYAASNVES 80
Qy 61 GIPARFSGSGSGTDFTLNIHPVEEEDAATYYCQQSNLDPWTFGGGTKLEIKRADAAPTVS 120
|:|||||||||||||:||||||||:| | |:|||| ||||||||||||||||||||||
Db 81 GVPARFSGSGSGTDFSLNIHPVEEDDIAMYFCQQSRKVPWTFGGGTKLEIKRADAAPTVS 140
Qy 121 IFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMS 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 141 IFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMS 200
Qy 181 STLTLTKDEYERHNSYTCEATHKTSTSPI 209
|||||||||||||||||||||||||||||
Db 201 STLTLTKDEYERHNSYTCEATHKTSTSPI 229
13. 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.
14. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Chang-Yu Wang whose telephone number is (571)272-4521. The examiner can normally be reached on Monday-Thursday, 7:00am-5:30pm EST.
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, Jeffrey Stucker, can be reached on 571-272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Chang-Yu Wang
October 7, 2025
/CHANG-YU WANG/Primary Examiner, Art Unit 1675