DETAILED ACTION
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 .
Status of Application, Amendments and/or Claims
1. Claims 1-71 have been canceled and new claims 72-91 have been added as requested in the preliminary amendment filed April 1, 2022. Following the amendment, claims 72-91 are pending in the present application.
2. Claims 72-91 are under examination in the current office action.
Information Disclosure Statement
3. The information disclosure statement (IDS) filed 05/09/2024 has been considered and the references therein are of record.
Specification
4. The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See p. 34, line 25 of the specification as originally filed. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
5. Applicant is advised that should claim 81 be found allowable, claim 82 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Rejections - 35 USC § 112
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.
6. Claims 84-91 are 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Each of claims 84-91 recites an effect that occurs upon administration of the anti-N3pGlu Ab antibody of claim 72. These limitations include: “wherein administration of the anti-N3pGlu Ab antibody causes reduction in Ab deposits in the brain of the patient” (claim 84); “wherein administration of the anti-N3pGlu Ab antibody causes slowing of cognitive decline in the patient” (claim 85); “wherein the Ab deposits in the brain of the patient are reduced by 35-100% within 6 months post treatment” (claim 86); “wherein 40-50% mean reduction in Ab deposits in the brain of the patient is achieved over 6 months post treatment” (claims 87); “wherein the reduction of Ab deposits in the brain of the patient is sustained for a period of 2 to 10 years post treatment” (claim 88); “wherein the reduction of Ab deposits in the brain of the patient is sustained for a period of 3 to 5 years post treatment” (claim 89); “wherein the reduction of Ab deposits in the brain of the patient is sustained for a period of at least 18 months after the last dose of the anti-N3pGlu Ab antibody” (claim 90); and “wherein the patients do not suffer from cerebral vasogenic edema or microhemorrhage upon administration of the anti-N3pGlu Ab antibody” (claim 91).
However, it is unclear whether assessing the patient following treatment with the anti-N3pGlu Ab antibody, such as for Ab deposits in the brain, etc., is required for infringement because methodology is implicit but there are no active method steps whereby these therapeutic outcomes are determined. Absent method steps, it is unclear what is required for direct infringement of these method claims. MPEP 2173.05(g) states: “the use of functional language in a claim may fail ‘to provide a clear-cut indication of the scope of the subject matter embraced by the claim’ and thus be indefinite.” It further states: “Examiners should consider the following factors when examining claims that contain functional language to determine whether the language is ambiguous: (1) whether there is clear cut indication of the scope of the subject matter covered by the claim; (2) whether the language sets forth well-defined boundaries of the invention or only states a problem solved or a result obtained; and (3) whether one of ordinary skill in the art would know from the claim terms what structure or steps are encompassed by the claim” (emphasis added). Since the claim fails to meet the criteria set forth in MPEP 2173.05(g), then the claims are indefinite.
This rejection may be obviated by Applicant stating on the record that the scope of the claim does not require, for infringement, assessing Ab deposits in the brain of a subject/testing cognition/etc. (i.e., the functional limitations of claims 84-91 as stated above).
Claim Rejections - 35 USC § 103
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.
7. Claims 72-91 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lu et al. (US 8,679,498 B2; issued Mar. 25, 2014) in view Ferrero et al. (WO 2016/087944 A2; published June 9, 2016; priority to 2014) (both references listed on IDS).
Lu et al. disclose and claim a method of treating a condition associated with A peptide activity in a human patient, comprising administering to the patient in need thereof an anti-N3pGlu A monoclonal antibody, wherein the condition is clinical or pre-clinical Alzheimer's disease (AD) (see claims 6-9 at cols. 80-81). Such teachings address the human patient of instant claims 72 and 73-74. Lu teaches that the antibody may be the B12L antibody, which is a humanized variant of the murine monoclonal antibody E8 (see col. 12, lines 10-12; Table 1 at col. 11). Importantly, this antibody comprises LCVR, HCVR, LC and HC sequences that are identical to the sequences of the instant invention, as shown below:
Antibody
Light Chain
Heavy Chain
B12L Instant application
28
29
Lu et al.
14
15
Accordingly, Lu teaches the therapeutic administration of an anti-N3pGlu A antibody identical to the antibody of present claim 72.
Lu further discloses that the chronic administration of an anti-N3pGlu A antibody to transgenic PDAPP mice, which are an animal model of Alzheimer's disease (AD), significantly reduced brain amyloid plaque deposition in aged 23-month-old PDAPP mice (see Example 6 at col. 14-15). Lu teaches, for instance, administering the anti-N3pGlu Ab antibody subcutaneously at 12.5 mg/kg weekly to the mice for three months (administering more than one dose over a period of 6 months or less, as in claim 72). Lu observed reductions in A plaques within the brains of the treated mice of about 38% to about 53% within three months of treatment, as compared to control-IgG treated mice, which is on point to the limitations of claims 84 and 86-87.
Further, Lu discloses that previous studies have demonstrated that treatment of aged PDAPP mice would result in an exacerbation of cerebral amyloid angiopathy (CAA)-related microhemorrage. However, Lu teaches that the anti-N3pGlu Ab antibody did not exacerbate cerebral amyloid angiopathy-related microhemorrhage in the aged PDAPP mice (see Example 7), which is on point to present claim 91. Thus, Lu provides for a method of treating AD in a subject comprising administering a humanized anti-N3pGlu A antibody, such as B12L, wherein the administering is sufficient to provide a reduction in A deposits in the brain of the subject without the subject suffering from cerebral vasogenic edema or microhemorrhage.
However, Lu does not teach that the dose is 10 mg/kg, the antibody is administered intravenously (claim 83), that 3-5 doses of the antibody are administered over a period of 6 months or less (or individually, 3, 4 or 5 doses are administered), the antibody is administered once every month/every 4 weeks, the AD is prodromal AD, or the patient carries one or two APOE e4 alleles.
Consistent with the disclosure of Lu, Ferrero et al. teach a method for the treatment of a human patient suffering from AD, including patients with preclinical, prodromal, mild, moderate, or severe AD (see [049]), comprising administering multiple sequential doses of an anti-A antibody. Ferrero teaches that whereas it is advantageous to use high doses of antibody for maximum effectiveness, the incidence of amyloid-related imaging abnormalities (ARIA) such as edema (ARIA-E) and hemorrhage (ARIA-H) can also increase when the doses of antibody are increased (see [0116]). Lu also teaches that the presence of the APOE e4 allele has been found to be a significant risk factor for ARIA-E ([010], and that patients treated according to the method may be ApoE4 carriers ([0101]), which addresses claim 76. Therefore, Ferrero recommends a sequential, step-wise increase in antibody dosages given at periodic intervals to mitigate potential ARIA-E or ARIA-H.
In one embodiment, for example, Ferrero teaches that 1-5 doses of 1 mg/kg of antibody are administered to the patient at intervals of about 4 weeks, followed by multiples doses of 3 mg/kg, 6 mg/kg and 10 mg/kg administered at 4 week intervals (see [020], [023] and [085]-[086]). A preferred effective amount is about 10 mg/kg (see [072]). The intravenous administration of a dose of 10 mg/kg is also taught at [0131]. Doses are taught to not exceed 60 mg/kg so as to reduce the occurrence of ARIA-E or ARIA-H in the brains of patients (see [073]). Such dosages and administration intervals are thus on point to the various limitations recited in present claims 77-82. Note that the present claims recite “comprising” language, and therefore there is nothing to preclude the administration of one or more lower dosages of antibody (i.e., at 1 mg/kg) prior to performing the method encompassed by the present claims. Ferrero teaches that the antibody is preferably administered by intravenous infusion (see [075] and [0104]), which addresses a limitation of claim 83.
Furthermore, Ferrero teaches that a statistically significant reduction in brain amyloid was observed at week 26 after the initial dose, and the effect appeared to continue to at least week 54 (see [0147]), which supports the expectation that performing a therapeutic method according to Ferrero would result in a sustained reduction in Abrain deposits for at least 18 months, 2-10 years, or 3-5 years, as recited in present claims 87-90 regarding the effects of the claimed therapy.
Accordingly, it would have been obvious to one of ordinary skill in the art to have applied the therapeutic dosing regimen of Ferrero to the treatment method of Lu and thereby arrive at the presently claimed invention. The motivation to do so comes from Ferrero, who teaches that the disclosed dosing method makes it possible to reduce the incidence of ARIA-E and/or ARIA-H in an AD patient treated with an anti-A monoclonal antibody. And even though the antibody used by Ferrero is different from the B12L antibody used by Lu, the skilled artisan at the time of filing would nonetheless have understood the risks posed by anti-A immunotherapy, including vasogenic edema and cerebral microhemorrhage, and would have sought methodology enhance the safety of the administered antibody. Given that Ferrero demonstrates such a dosage regimen to be effective in reducing or eliminating the incidence of the noted potential adverse events (i.e., ARIA-E and/or ARIA-H), the artisan would have had a reasonable expectation that the dosage regimen of Ferrero could be successfully applied to treatment with the B12L antibody of Lu. Accordingly, the cited references render obvious the invention of present claims 72-91.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
8. Claims 72-91 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 9-10 and 13-18 of U.S. Patent No. 11,312,763. Although the claims at issue are not identical, they are not patentably distinct from each other because in each case the claims encompass the therapeutic administration of the same dosage (10 mg/kg) of the same anti-N3pGlu Ab antibody to a human patient having Alzheimer’s disease (AD) over the same period of time. The patented claims further recite that the level of Ab deposits in the brain of the patient are reduced by 35-100% within 6 months of administration of the antibody, this reduction is sustained for at least 18 months, and that 3-5 doses of the antibody are given over a period of 6 months or less. Thus, the patented ‘763 claims teach or render obvious the method of the present claims.
9. Claims 72-91 are rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 1-9 of U.S. Patent No. 8,679,498;
claims 1-3 of U.S. Patent No. 9,999,624; and
claims 1 and 4-9 of U.S. Patent No. 10,988,529 (previously 16/321,278),
each in view of Lu et al. (US 8,679,498 B2; cited above) and Ferrero et al. (WO 2016/087944 A2; cited above).
The claims of the ‘498, ‘624 and ‘529 patents are directed to methods of treating a patient having clinical, preclinical, or prodromal AD comprising administering an anti-N3pGlu A antibody. The antibody recited by the patented ‘498, ‘624 and ‘529 claims is the antibody of present claims. The difference, therefore, between the patented claims and the present claims is that the patented claims do not recite an administration regimen comprising the presently recited dosages and frequency of administration.
The teachings of Lu et al. and Ferrero et al. are described above and collectively teach administration and dosage regimens for therapeutic anti-A antibodies for the treatment of AD. These teachings provide for therapeutically effective dosages of administered antibody of 10 mg/kg, within the time period of 6 months, frequency of administration (every 4 weeks), and with eliciting therapeutic effects consistent with the present claims.
Therefore, it would have been obvious to one of ordinary skill in the art to have modified the therapeutic methods of the ‘498, ‘624 or ‘529 patented claims according to the prior art teachings of Lu and Ferrero and thereby arrive at the presently claimed invention. This is because the artisan has good reason to pursue the known options within his or her technical grasp to obtain predictable results. Such would amount to combining of prior art elements according to known methods to yield predictable results.
Conclusion
10. No claims are allowed.
Advisory Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kimberly A. Ballard whose telephone number is (571)272-2150. The examiner can normally be reached Mon-Fri 8AM - 5PM EST.
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/KIMBERLY BALLARD/Primary Examiner, Art Unit 1675
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