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
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 April 8, 2026 has been entered.
RESPONSE TO AMENDMENT
Status of Application/Amendments/claims
3. Applicant’s amendment filed April 8, 2026 and May 13, 2026 is acknowledged. Claims 5-12, 15-16, 18-24 and 30-32 are cancelled. Claims 1, 4, 17, 26 and 29 are amended. Claims 33-47 are newly added. Claims 1-4, 13-14, 17, 25-29 and new claims 33-47 are pending in this application. Election was made without traverse in the reply filed on January 21, 2025.
4. Claims 1-4, 13-14, 17 25-29, and 33-47 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.
5. Applicant’s arguments filed on April 8, 2026 and May 13, 2026 have been fully considered but they are not deemed to be persuasive for the reasons set forth below.
Priority
6. 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.
Claim Rejections/Objections Withdrawn
7. 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1-4, 13-17, 25-29 and 31 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in response to Applicant’s amendment to the claims and cancelation of claims 15-16 and 31.
Claim Rejections/Objections Maintained
In view of the amendment filed on April 8, 2026 and May 13, 2026, the following rejections are maintained.
Claim Rejections - 35 USC § 112
8. 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, 13-14, 17 25-29, and 33-47 are 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 ApoE3-induced 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 antibody 7C11 comprising a VH and a VL having recited SEQ ID NOs: 17-18, 9 and SEQ ID NOs: 4-6 for HCDRs1-3 and LCDRs1-3 respectively into the eye of the mouse compared to no treatment or a vehicle IgG control, does not reasonably provide enablement for methods for reducing ApoE-induced paired helical filament (PHF) tau formation in a human subject in need thereof with all possible conditions, treating Alzheimer’s disease in a human subject in need thereof and inhibiting binding of heparan sulfate proteoglycans (HSPGs) or glycosaminoglycans (GAGs) to ApoE in a human subject in need thereof with all possible conditions using the claimed antibody comprising a VH and a VL having recited SEQ ID NOs: 17-18, 9 and SEQ ID NOs: 4-6 for HCDRs1-3 and LCDRs1-3 respectively 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, 13-14, 17, 25-29 and 33 as amended are drawn to a method of reducing ApoE-induced PHF tau formation in a human subject in need thereof, comprising administering to the human subject 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.
Claims 34-39 as amended are drawn to a method of treating Alzheimer’s disease in a human subject in need thereof, comprising administering to the human subject the claimed antibody or antigen-binding portion thereof as set forth above.
Claims 40-47 as amended is drawn to a method of inhibiting binding of HSPG or GAGs to ApoE in a human subject in need thereof, comprising administering to the human subject a therapeutically effective amount of the claimed antibody or antigen-binding portion thereof as set forth above.
Response to Arguments
On p. 10-18 of the response, Applicant argues that: i) the rejection has been overcome in view of amendment to claim 1 by reciting reducing ApoE-indued PHF tau formation, and treating Alzheimer’s disease and inhibiting binding of HSPGs or GAGs to ApoE as in new claims because ApoE-HSPG interactions represent a mechanistically coherent target in tauopathy-associated diseases such as AD and frontotemporal dementia (FTD) and cites Bugiani et al. (1999; 58:667-77) cited at p.96, line 15 of the specification; ii) Example 9 of the specification provides support for enabling the use of an anti-ApoE antibody for treating AD and other tauopathies associated with ApoE-induced PHF tau formation such as FTD because Example 9 showed that an anti-ApoE antibody, antibody 1H4-2 was effective in reducing phosphorylated tau (PHF) in a mouse model, B6;C3-Tg(Prnp-MAPT*P301S)PS19Vle/J mouse, which contains a human tau P301S mutation and is a validated animal model for AD and other tauopathies such as FTD; iii) Marino et al. (Alzheimer’s Dement. 2024; 20:819-836) demonstrates that the anti-ApoE antibody 7C11 can cross the blood-brain barrier and reduce levels of pTauS396 after systemic administration in another mouse model of AD, an ApoE4 knock-in (KI) mouse, B6.129P2-Apoetm3(APOE*4) Mae N8 (see Figure 5A-G; 5E); iv) antibody 1H4-2 and antibody 7C11 only differ in VH CDR1 and VH CDR2 and would be expected to function similarly to antibody 1H4-2 because 1) both were generated by immunizing with ApoE: KLH-CTEELRVRLASHLRK-CONH2, 2) reduced binding to ApoE3 to heparin (Fig.18A and 23A), and 3) antibody 1H4-2 was effective at reducing ApoE-dependent induction of PHF-tau in a mouse model of AD, B6;C3-Tg(Prnp-MAPT*P301S)PS19Vle/J mouse (Figures 43B-C and F-G); and antibody 7C11 reduced ApoE3-induced PHF-tau in the mouse model of AD, B6;C3-Tg(Prnp-MAPT*P301S)PS19Vle/J mouse (Figure 4E-G in Marino). Applicant further cites Schroeder et al. (Vaccine, 1998; 16:1383-90), p. 92, lines 13-15, p. 93, lines 5-7, Figures 18A and 23A, 43B-C and F-G of the specification and Figure 4G of Marino, In re Borkowski, Allergan, Inc. v. Sandoz, Inc., MPEP2164.02, Alcon Research Ltd. V. Barr Labs., Inc., Cephalon, Inc. v. Watson Pharms, Inc. in support of the arguments.
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. There is no well-established structural and functional relationship or correlation between ApoE3-induced PHF-tau formation by intravitreally injection of human ApoE3 into a retina of an eye in a B6;C3-Tg(Pmp-MAPT*P301S)PS19Vle/J mouse and all forms of APOE-induced PHF-tau formation in all forms of diseases, all forms of AD or all forms of tauopathies caused by other mechanisms.
There is no well-established structural and functional relationship or correlation between B6;C3-Tg(Pmp-MAPT*P301S)PS19Vle/J mouse and all forms of diseases, all forms of AD or all forms of tauopathies caused by other mechanisms.
There is also no well-established structural and functional relationship or correlation between ApoE4-KI mouse, B6.129P2-Apoetm3(APOE*4) Mae N8 in the reference of Marino and all forms of diseases, all forms of AD or all forms of tauopathies caused by other mechanisms.
The data shown in the Example 9 or in the reference of Marino is based on B6;C3-Tg(Pmp-MAPT*P301S)PS19Vle/J mouse which express the P301S mutant form of human microtubule-associated protein tau (MAPT), under the control of mouse prion protein promoter (Prnp).
The reduced levels of human ApoE3-induced PHF tau formation by the claimed antibody 7C11 (comprising a VH comprising recited SEQ ID NOs: 17-18 and 9 for HCDRs1-3 respectively and a VL comprising recited SEQ ID NOs: 4-6 for LCDRs1-3 respectively) in the B6;C3-Tg(Pmp-MAPT*P301S)PS19Vle/J mouse as shown in the reference of Marino is based on injection of human ApoE3 into a human MAPT-P301S-transgenic mouse which is under a background of carrying a human MAPT-P301S-mutation.
Based on Applicant’s own admission, ApoE2 is protective for AD, ApoE3 allele is neutral to AD (p. 12 of the instant specification) and ApoE3ch (R136S) in PSEN1-E280A mutation carriers is resistant to AD (p. 62 of the instant specification). 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 reduce all forms of ApoE-induced PHF tau formation in all possible conditions including all forms of AD or all forms of tauopathies.
Further, ApoE-induced PHF tau in a human MAPT-P301S-transgenic mouse or hyperphosphorylated tau or pTauS396 in an ApoE4-KI mouse is not the only cause for AD because there are several mechanisms and genes are involved in pathogeneses of AD. They include ageing, inflammation and immune response, APP, presenilin1/2, ApoE and genes involved in the amyloid cascade, genes involved in the mitochondrial cascade as taught by Swerdlow (p. 348-344, Swerdlow, Clin. Interv. Ageing 2007; 2:347-359, cited previously), Atwood et al. (p. abstract; Atwood et al., J. Alzheimer’s Disease; 2015; 47:33-47, cited previously) and Henstridge et al. (p. 95-103; Henstridge et al., Nat. Rev. Neurosci. 2019; 20: 94-107, cited previously). Each type of animal models of 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). For example, an animal model of APOE3-induced PHF tau formation in a mouse carrying a transgene of human MAPT-P301S-mutation can only be used for screening or evaluation for inhibiting the formation of APOE3-induced PHF tau but not for evaluating brain amyloidosis induced by A or generation of A caused by -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 or in the reference of Marino 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 a transgenic mouse carrying a human tau P301S mutation, i.e. a B6;C3-Tg(Pmp-MAPT*P301S)PS19Vle/J mouse, induced by human APOE3. The inducible APOE-dependent hyperphosphorylation in PHF tau is based on the injection of human ApoE3 into transgenic mouse carrying a human tau P301S mutation, a combination and interaction of human ApoE3 with human tau-P301S mutation.
Moreover, 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, cited previously). 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 hyperphosphorylated tau or ApoE-induced PHF tau formation is not the only cause of cognitive dysfunction or dementia in AD. Thus, it is unpredictable whether administration of the claimed antibody can treat AD or tauopathies caused by other mechanisms.
ii. Neither the specification nor the reference of Marino provides support to demonstrate that administration of the claimed antibody can inhibit binding HSPG or GAGs to ApoE including all forms of ApoE in vivo including all forms of tauopathies associated with ApoE-induced PHF tau formation and AD or FTD.
Applicant obviously intended to inhibit binding HSPG or GAGs to all forms of ApoE in all forms of diseases and conditions in vivo using the claimed antibody.
However, Based on Applicant’s own admission and the data shown in post-filing reference, Marino et al. (2024), the antibody 7C11 comprising a VH comprising recited SEQ ID NOs: 17-18 and 9 for HCDRs1-3 respectively and a VL comprising recited SEQ ID NOs: 4-6 LCDRs1-3 respectively can bind to ApoE3 and ApoE4 and does not bind to ApoE3ch (p. 826, 2nd col., 2nd-3rd paragraphs in Marino) and ApoE3ch does not interact with HSPG (see p.71 of the instant specification); and only reduced human APOE3-induced PHF-tau accumulation induced by injection of human APOE3 into a retina of an eye of a transgenic mouse carrying a human tau P301S mutation (B6;C3-Tg(Pmp-MAPT*P301S)PS19Vle/J mouse) when compared to no treatment. Based on the data shown in post-filing reference of Marino et al. (2024), there is no statistical difference between treatment with the 7C11.ChIgG1 antibody+ApoE4 and heparin+ApoE4 in SH-SY5Y cells in vitro (see p. 831, figure 4C).
The specification provides insufficient guidance or no data to support that administration of the claimed antibody can inhibit binding HSPG or GAGs to ApoE including all forms of ApoE in vivo in all possible conditions caused by all possible mechanisms. Thus, 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) by the claimed antibody compared to no treatment can be applied to inhibiting binding HSPG or GAGs to all forms of ApoE in all forms of diseases and conditions caused by all possible mechanisms in vivo. 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.
iii. Claim 17 encompasses a structurally and functionally undefined genetic mutation in ApoE4, ApoE3, PSEN1, PSEN2, APP, MAPT and any combination thereof.
Claim 33 encompasses a ApoE3 gene mutation encoding ApoE3-R136S.
Based on Applicant’s own admission, ApoE2 is protective for AD and ApoE3 allele is neutral (p. 12 of the instant specification) and ApoE3ch (R136S) in PSEN1-E280A mutation carriers is resistant to AD (p. 62 of the instant specification).
The specification provides no structural and functional relationship between the undefined mutation in ApoE4, ApoE3, PSEN1, PSEN2, APP, MAPT or any combination thereof and APOE3-induced PHF-tau formation in a transgenic mouse carrying a human tau P301S mutation and induced by injection of human ApoE3. Thus, a skilled artisan cannot contemplate what genetic mutation in ApoE4, ApoE3, PSEN1, PSEN2, APP, MAPT or any combination thereof can result in ApoE-induced PHF tau formation because ApoE3ch (R136S) in PSEN1-E280A mutation carriers is resistant to AD and does not have PHF-tau formation as admitted by Applicant.
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 methods of reducing ApoE-induced PHF tau formation, treating AD and inhibiting binding a HSPG or GAGs to ApoE in a human subject in need thereof in vivo in all forms of diseases and conditions by the claimed antibody comprising a VH comprising recited SEQ ID NOs: 17-18 and 9 for HCDRs1-3 respectively and a VL comprising recited SEQ ID NOs: 4-6 LCDRs1-3 respectively.
Accordingly, the rejection of claims 1-4, 13-14, 17 25-29, and 33-47 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
9. Claims 1-4, 13-14, 17 25-29, and 33-47 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for 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, 13-14, 17 25-29, and 33-47 as amended encompass using the claimed antibody for reducing ApoE-induced PHF tau formation and inhibiting binding HSPG or GAGs to ApoE in vivo in a genus of all possible conditions, and treating AD.
Response to Arguments
On p. 18-19 of the response, Applicant argues that the specification provides support for the claimed methods recited in instant claims that are directed to reducing ApoE-induced PHF tau formation in a human subject including tauopathies and conditions associated with ApoE-induced PHF tau formation, and cites Example 9 on p.96-98 in support of the arguments.
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 reducing all forms of ApoE-induced PHF tau formation and inhibiting binding HSPG or GAGs to all forms of ApoE in vivo in a genus of all possible conditions or treating all forms of AD using the claimed antibody because:
i. There is no well-established structural and functional relationship or correlation between ApoE3-induced PHF-tau formation by intravitreally injection of human ApoE3 into a retina of an eye in a B6;C3-Tg(Pmp-MAPT*P301S)PS19Vle/J mouse and all forms of APOE-induced PHF-tau formation in all forms of diseases, all forms of AD or all forms of tauopathies caused by other mechanisms.
ii. There is no well-established structural and functional relationship or correlation between B6;C3-Tg(Pmp-MAPT*P301S)PS19Vle/J mouse and all forms of diseases, all forms of AD or all forms of tauopathies caused by other mechanisms.
iii. There is also no well-established structural and functional relationship or correlation between ApoE4-KI mouse, B6.129P2-Apoetm3(APOE*4) Mae N8 shown in the reference of Marino and all forms of diseases, all forms of AD or all forms of tauopathies caused by other mechanisms.
iv. Neither the specification nor the reference of Marino or other prior art provides support to demonstrate that administration of the claimed antibody can inhibit binding HSPG or GAGs to ApoE including all forms of ApoE in vivo including all forms of tauopathies associated with ApoE-induced PHF tau formation and AD or FTD.
v. Claim 17 encompasses using a genus of structurally and functionally undefined genetic mutation in ApoE4, ApoE3, PSEN1, PSEN2, APP, MAPT or any combination thereof.
Based on Applicant’s own admission, ApoE2 is protective for AD and ApoE3 allele is neutral (p. 12 of the instant specification) and ApoE3ch (R136S) in PSEN1-E280A mutation carriers is resistant to AD (p. 62 of the instant specification).
The specification provides no structural and functional relationship between the undefined mutation in ApoE4, ApoE3, PSEN1, PSEN2, APP, MAPT or any combination thereof and APOE3-induced PHF-tau formation in a transgenic mouse carrying a human tau P301S mutation and induced by injection of human ApoE3. However, claim 33 recites a ApoE3 gene mutation encoding ApoE3-R136S, which is ApoE3ch (R136S), and ApoE3ch (R136S) in PSEN1-E280A mutation carriers is resistant to AD and does not have PHF-tau accumulation. Thus, a skilled artisan cannot contemplate what genetic mutation in ApoE4, ApoE3, PSEN1, PSEN2, APP, MAPT or any combination thereof can result in ApoE-induced PHF tau formation because ApoE3ch (R136S) in PSEN1-E280A mutation carriers is resistant to AD and does not have PHF-tau formation as admitted by Applicant.
Since the common characteristics/features of other forms of APOE-induced PHF-tau formation in all forms of diseases, all forms of AD or all forms of tauopathies caused by other mechanisms 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 claimed antibody for reducing all forms of APOE-induced PHF-tau formation in all forms of diseases, all forms of AD or all forms of tauopathies caused by other mechanisms, inhibiting binding HSPG or GAGs to ApoE including all forms of ApoE in vivo including all forms of tauopathies associated with ApoE-induced PHF tau formation and all forms of AD or FTD.
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).
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.
Accordingly, the rejection of claims 1-4, 13-14, 17 25-29, and 33-47 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
10. 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
11. 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
12. 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 Monday-Thursday, 7:00am-5:00pm 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 at 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
May 16, 2026
/CHANG-YU WANG/Primary Examiner, Art Unit 1675
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