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 1-37 are pending and under examination in the current office action.
Information Disclosure Statement
2. The information disclosure statements (IDSs) filed 08/26/2022 and 02/06/2023 have been considered and the references therein are of record.
Priority
3. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. 16/820,546, filed on 05/16/2018.
Claim Objections
4. Claims 4-17 and 24-37 are objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim cannot depend from any other multiple dependent claim. See MPEP § 608.01(n). Accordingly, the claims have not been further treated on the merits.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
5. Claim(s) 1-3 and 18-20 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Barbour et al. (WO 2015/155694 A1).
Claim interpretation: For the purpose of applying art, the recitation in claim 1 of an antibody “for use in the treatment of a neurological disorder….wherein the treatment has reduced side effect after administration, wherein the administration is an intravenous, subcutaneous, or intramuscular administration, wherein the side effect is an administration-related side effect, and wherein the side effect is one or more selected from the group consisting of vasodilation, bronchoconstriction, laryngeal edema, drop of cardiac pressure, and hypothermia” are all considered intended uses of the antibody, and therefore do not structurally limit the claimed antibody unless otherwise noted for a particular dependent claim. MPEP § 2173.05(g), Functional Limitations, states that “[i]f a prior art structure is capable of performing the intended use as recited in the preamble, then it meets the claim. See, e.g., In re Schreiber, 128 F.3d 1473, 1477, 44 USPQ2d 1429, 1431 (Fed. Cir. 1997) (anticipation rejection affirmed based on Board’s factual finding that the reference dispenser (a spout disclosed as useful for purposes such as dispensing oil from an oil can) would be capable of dispensing popcorn in the manner set forth in appellant’s claim 1 (a dispensing top for dispensing popcorn in a specified manner)) and cases cited therein. See also MPEP § 2112 – § 2112.02.
For the same reasoning, the limitations of dependent claims 2-3 are interpreted as intended uses of the antibody of claim 1. Regardless, teachings with respect to the recited limitations will be addressed below.
Barbour et al. teach a therapeutic method for treating a neurodegenerative disease, comprising administering a blood-brain barrier shuttle comprising a bispecific antibody comprising a monoclonal antibody specific for human alpha-synuclein (alpha-SN) linked to a monovalent binding entity that binds to the transferrin receptor (TfR) (see abstract, [0019], [0133] and [0214]). See also Figure 13 of Barbour, reproduced here, wherein the 5C1 antibody binds alpha-SN and the 8D3 sFab binds TfR:
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Barbour teaches that the brain effector entity antibody (i.e., the alpha-SN antibody) includes the Fc region of a heavy chain, and the monovalent binding entity (i.e., the anti-TfR sFab) is coupled to the C-terminal end of the Fc region of the heavy chain (see [0023]). Taken with the above Figure 13, therefore, the bispecific molecule thus comprises: an Fc-region; two binding sites that specifically bind to a first target (i.e., the top of the Y-structure of the anti-alpha-SN 5C1 antibody); and one binding site that specifically binds to a second target (i.e., the 8D3 sFab that binds to TfR) as in present claims 1 and 18, as well as treatment of a neurological disorder as in claim 18.
Regarding claims 2, 18 and 20, Barbour teaches that the blood-brain barrier (BBB) shuttle (i.e., the bispecific antibody molecule of Figure 13 above) may be administered by intravenous, subcutaneous or intramuscular routes (see [0241]), or by infusion ([0240]).
Finally, with respect to the limitation in claim 18 reciting that the treatment has reduced administration-related side effect after administration, wherein the side effect is vasodilation, bronchoconstriction, laryngeal edema, drop of cardiac pressure or hypothermia, and in claims 3 and 19 reciting that “the treatment has a reduced side effect after administration as compared to a treatment with the same antibody lacking one or two of said binding sites specifically binding to the first (cell surface) target”, it is noted that because the same agent (i.e., a bispecific antibody comprising an anti-alpha synuclein antibody linked to an anti-TfR Fab) is being administered to the same patient population (i.e., patients having LBD, PD, AD, etc.) for the same purpose (i.e., therapy), the treatment taught by Barbour would be expected to inherently have reduced side effects after administration as claimed. A chemical composition and its properties are inseparable (In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963)), as are their processes and yields (In re Von Schickh, 362 F.2d 821, 150 USPQ 300 (CCPA 1966)). Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
Furthermore, MPEP § 2112 (I) states “[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus, the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). The instant specification notes, for example, that a construct according to the claims comprising a first antibody having two binding sites to a first target, and another monovalent binding site for TfR1 linked at the C-terminus of the first antibody heavy chain, has attenuated Fc-region-FcyR interactions when bound to TfR1, and thus reduced or absent infusion reactions (i.e., side effects such as hypothermia). See, for instance, paragraph [00101] of the instant specification. Therefore, because the structure of the bispecific antibody construct disclosed by Barbour is the same as that presently claimed, the therapeutic administration of the antibody construct as taught by Barbour would inherently have reduced side effects as claimed.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
6. Claims 21-23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Barbour et al. (WO 2015/155694 A1) in view of Vogel et al. (Clin. J. Oncol. Nursing, 2010, 14(2):E10-E21), Palabrica et al. (Asia Pacific Allergy, 2013, 3:249-256), and New Zealand Clinical Immunology Group (NZCIG) (Nursing guidelines for administration of intravenous immunoglobulin (IVIg), Oct 2013, 7 pages) (all listed on 08/26/2022 IDS).
The reasons why the teachings of Barbour et al. anticipate the invention of present claims 1-3 and 18-20 are discussed above. In brief, Barbour provides for a method of treating a neurodegenerative disease comprising administering a blood-brain barrier (BBB) shuttle comprising a bispecific antibody comprising a monoclonal antibody specific for human alpha-synuclein (alpha-SN) linked to a monovalent binding entity that binds to the transferrin receptor (TfR) (see abstract, [0019], [0133] and [0214]). Barbour further teaches that the bispecific antibody can be administered by infusion (0240]-[0241]). However, Barbour does not expressly teach that the infusion rate is ≥50 ml/h, or ≥100 ml/hr, or ≥150 ml/hr as in claims 21-23, respectively.
The teachings of Vogel et al., Palabrica et al. and NZCIG are commensurate and thus will be presented together. In particular, Vogel et al. provide a review of infusion reactions most commonly observed following monoclonal antibody therapy. Vogel teaches that monoclonal antibodies, such as those administered for cancer therapy, have a unique side-effect profile that includes the potential for non-allergic infusion reactions caused by cytokine release (see abstract). Vogel indicates that the route and rate of administration, drug form, whether the drug is given in combination or as a single agent, and concomitant medications all influence a person’s risk for a reaction (see p. E15, right column). For the monoclonal antibody rituximab, for instance, Vogel teaches that a slow initial rate of infusion is recommended to reduce the risk of infusion reactions, such as starting at 50 mg per hour and increasing the dose by increments of 50 mg/hr every 30 minutes to a maximum of 400 mg/hr (see p. E15, left column).
Similarly, Palabrica et al. teach that intravenous immunoglobulin (IVIG) infusions are also associated with some adverse events, most of which can be managed by reducing the rate of infusion (see abstract). For example, Palabrica indicates that hypothermia, hypotension (i.e., drop of cardiac pressure), fever, rash, chills, cyanosis, irritability, vomiting, chest pain and dyspnea were the most commonly observed adverse reactions in patients administered various IVIG preparations (see Table 2 at p. 253). Palabrica teaches that the rate of IVIG infusions should be low at the beginning and increased every 15-30 minutes, based on the patient’s tolerance. For example, a 5% solution of IVIG is initially infused at a rate of 0.5 ml/kg/hr, and if this is tolerated, infusion rate is gradually increased to a maximum of 4 ml/kg/hr (see p. 250, right column, 2nd paragraph). For an average adult weighing approximately 70 kg, then this would equate to an initial rate of about 35 ml/hr increasing to a maximum rate of about 280 ml/hr.
Consistent with the teachings of Palabrica, NZCIG provides practical guidelines to one of ordinary skill in the art for the administration of IVIG. NZCIG indicates that although adverse reactions are relatively rare, if IVIG is given too quickly, aggregates of immunoglobulin may form causing the complement system to be activated. This may result in chills, chest pain and headaches. Therefore, NZCIG states, infusions must always be started slowing and gradually increased (see p. 2 under “Adverse Reactions and Risks”). For adult patients receiving their first infusion, it is recommended that IVIG be infused at rates according to the following regimen: 30 ml/hr for 30 minutes; 60 ml/hr for 30 minutes; 90 ml/hr for 30 minutes; 120 ml/hr for 30 minutes; 150 ml/hr for 30 minutes; and finally 180 ml/hr for 30 minutes. Subsequent infusions can be performed according to the regimen of: 60 ml/hr for 15 minutes; 120 ml/hr for 15 minutes; 180 ml/hr for 15 minutes; and finally 240 ml/hr for 15 minutes. See table of “Adult Rates of Infusion” at p. 5.
Thus, the combined teachings of Vogel, Palabrica and NZCIG provide guidance in the art regarding infusion rates for administering antibody therapy, such as for specific monoclonal antibodies or IVIG treatments. The rates taught and suggested by these references are directly on point to the ≥50 ml/h, ≥100 ml/hr, and ≥150 ml/hr rates that are recited in current claims 21-23.
Accordingly, given the guidance provided in the combined teachings of Vogel, Palabrica and NZCIG, it would have been obvious to one of ordinary skill in the art to have administered the bispecific antibody of Barbour at a slow initial rate that incrementally increases to achieve a rate of at least 180 ml/hr, and thereby arrive at the presently claimed invention. The motivation to do so comes from each of the Vogel, Palabrica, and NZCIG references that teach that in order to reduce or prevent adverse events associated with the administration of antibodies to a patient, infusion rates should start slowly and gradually be increased. Given that the BBB shuttle of Barbour is an antibody molecule and thus subject to causing similar adverse reactions in patients as reported in Vogel, Palabrica and NZCIG, the artisan would have recognized that an infusion rate that starts slow and gradually increases would be the most practical regimen for reducing the incidence of adverse events. Therefore, infusion of the BBB shuttle bispecific antibody of Barbour at a rate of is ≥50 ml/h, or ≥100 ml/hr, or ≥150 ml/hr would have been obvious and predictable. 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 the combining of prior art elements according to known methods (i.e., antibody infusion rates) to achieve a predictable outcome.
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.
7. Claims 1-3 and 18-23 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.
The phrases “first (cell surface) target” and/or “second (cell surface) target” in each of claims 1, 3, 18 and 19 renders the claims indefinite because it is unclear whether the claims are limited to the phrase “cell surface” within the parentheses or whether this phrase is merely exemplary of the type of target to which the antibody binding sites bind. The metes and bounds of the claims therefore cannot be readily determined.
Dependent claims 2 and 20-23 have been included in this rejection because they contain all of the limitations of base claims 1 or 18, yet nothing in addition that would aid in clarifying the issue.
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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
8. Claims 1-3 and 18-20 rejected on the ground of nonstatutory double patenting as being unpatentable over:
Claims 1-5 and 8-13 of U.S. Patent No. 10,941,205;
Claims 1-5 of U.S. Patent No. 11,787,868;
Claims 1-2 of U.S. Patent No. 12,358,997; and
Claims 1-5 of U.S. Patent No. 11,603,411.
Although the claims at issue are not identical, they are not patentably distinct from each other because in each case the claims encompass bispecific antibodies comprising a full length antibody (which contains two pairs each of a light chain and a heavy chain, which therefore contains two binding sites and an Fc region; i.e., two binding sites specifically binding a first target; an Fc-region) and an Fab fragment (i.e., one binding site specifically binding to a second target). In the case of the ‘205, ‘868 and ‘997 patents, the first target is amyloid-beta, and the second target is transferrin receptor (TfR). The claims of these patents also recite a method for the treatment of an individual having Alzheimer’s disease (AD)(i.e., a neurological disorder) by administering the bispecific antibody, or else this is disclosed as a use of the antibody by the specification of the ‘997 patent. Each of these three patents also defines administration to include by means of infusion.
The courts have held that a "claim to a method of using a composition is not patentably distinct from an earlier claim to the identical composition in a patent disclosing the identical use," which extend to any and all such uses disclosed in the specification of the earlier patent. Pfizer, Inc. v. Teva Pharmaceuticals USA, Inc., 518 F.3d at 1363 (Fed. Cir. 2008), and Geneva Pharmaceuticals, Inc. v. GlaxoSmithKline PLC, 349 F.3d at 1385-86 (Fed. Cir. 2003). Indeed, as both cases recognized,
[i]t would shock one’s sense of justice if an inventor could receive a patent upon a composition of matter, setting out at length in the specification the useful purposes of such composition, … and then prevent the public from making an beneficial use of such product by securing patents upon each of the uses to which it may be adapted.
Sun Pharmaceuticals Industries, Ltd. v. Eli Lilly and Co., 611 F.3d 1381 (Fed, Cir. 2010), citing Pfizer, 518 F.3d at 1363 n.8 (emphases added); and Geneva, 349 F.3d at 1386 (quoting In re Byck, 48 F.2d 665, 666 (CCPA 1931)).
The bispecific antibody of the ‘411 patent claims is recited to comprise two binding sites specific for the cell surface target of CD20, and one binding site specific for the cell surface target TfR. The ‘411 claims also recite a method of treating multiple sclerosis (i.e., a neurological disorder) comprising administering the bispecific antibody. As above, the specification of the ‘411 patent defines administration to include infusion.
9. Claims 1-3 and 18-20 rejected on the ground of nonstatutory double patenting as being unpatentable over:
Claims 1-8 of U.S. Patent No. 9,493,553;
Claims 1-8 of U.S. Patent No. 9,670,274;
Claims 1-8 of U.S. Patent No. 9,890,209; and
Claims 1-8 of U.S. Patent No. 10,316,082.
Although the claims at issue are not identical, they are not patentably distinct from each other because in each case the claims encompass bispecific antibodies comprising a full length antibody (which contains two pairs each of a light chain and a heavy chain, which therefore contains two binding sites and an Fc region; i.e., two binding sites specifically binding a first target; an Fc-region) and an Fab fragment (i.e., one binding site specifically binding to a second target). In each of the above listed patents, the bispecific antibody of the patented claims comprises a first target (alpha-synuclein) and a second target (an anti-blood-brain-barrier antibody fragment that binds to LRP1, LRP8, human transferrin receptor (TfR) or human insulin-like growth factor receptor). The patented claims further recite that the antibody comprises an Fc region (such as of the human subclass IgG4) (i.e., having reduced side effects after administration). The patented claims also recite a method for treating synucleinopathy or Parkinson’s disease (PD), which is a neurological disorder. Finally, each of the above patents defines administration to include infusion. Therefore, the patented claims teach or render obvious the presently claimed invention.
10. Claims 1-3 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 3-9 of copending Application No. 18/294,139 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because in each case the claims encompass a bispecific antibody comprising an Fc-region, two binding sites that specifically bind a first cell surface target (anti-PD-1 antibody, or two anti-PD-1 Fabs), and one binding site that specifically binds a second cell surface target (an anti-TfR Fab fragment).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
11. No claims are allowed.
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/KIMBERLY BALLARD/Primary Examiner, Art Unit 1675
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