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 .
Claims 1-20 are pending.
Applicant’s election of (A) brain tissue as species of tissue, (B) human glucocerebrosidase as the species of brain target, (C) monkey as the species of experimental animal in the reply filed on April 30, 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 1-20, drawn to a method for determining the concentration of a therapeutic antibody in a tissue of an experimental animal that read on (A) brain tissue as species of tissue, (B) human glucocerebrosidase as the species of brain target, (C) monkey as the species of experimental animal, are being acted upon in this Office Action.
Priority
Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d), which papers have been placed of record in the file.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on June 27, 2024 has been considered by the examiner and an initialed copy of the IDS is included with this Office Action.
Drawings
The drawings were received on February 2, 2024. These drawings are acceptable.
Abstract
The abstract of the disclosure is objected to because the abstract is too long and exceeds 150 words in length. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
Applicant is reminded of the proper content of an abstract of the disclosure.
A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art.
If the patent is of a basic nature, the entire technical disclosure may be new in the art, and the abstract should be directed to the entire disclosure. If the patent is in the nature of an improvement in an old apparatus, process, product, or composition, the abstract should include the technical disclosure of the improvement. The abstract should also mention by way of example any preferred modifications or alternatives.
Where applicable, the abstract should include the following: (1) if a machine or apparatus, its organization and operation; (2) if an article, its method of making; (3) if a chemical compound, its identity and use; (4) if a mixture, its ingredients; (5) if a process, the steps.
Extensive mechanical and design details of an apparatus should not be included in the abstract. The abstract should be in narrative form and generally limited to a single paragraph within the range of 50 to 150 words in length.
See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
Specification
Applicants should amend the first line of the specification to update the relationship between the instant application and 17/136,289, filed December 29, 2020, which is now U.S. Pat No. 11,913,945.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant's cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim rejections under - 35 U.S.C. 112
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 1-20 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 MPEP § 2163 lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include: the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
For claims drawn to a genus, MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus, See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406, M.P.E.P. § 2163, II, A, 3, (a), (ii).
Claim 1 encompasses a method for determining the concentration of a therapeutic antibody in any tissue of an experimental animal, whereby the tissue has a barrier to the blood circulation of said animal and whereby the therapeutic antibody had been administered to said experimental animal, wherein the interference from residual blood in a tissue sample of the experimental animal, which is used for determining the concentration of the therapeutic antibody in said tissue, is reduced, the method comprising the following steps
i) determining the concentration of the therapeutic antibody in a blood sample of the experimental animal,
ii) determining the concentration of the therapeutic antibody in the tissue sample of the experimental animal,
iii) determining the concentration of an inert reference antibody in the blood sample of the experimental animal,
iv) determining the concentration of the inert reference antibody in the tissue sample of the experimental animal,
v) determining the tissue concentration in the tissue sample,
and determining the concentration of the therapeutic antibody in the tissue of the experimental animal with the following formula:
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- whereby the inert reference antibody does not cross said barrier between the tissue and the blood circulation,
- whereby the inert reference antibody had been administered i) either together with the therapeutic antibody in case the sample is to be taken within 5 minutes after the administration of the therapeutic antibody, or ii) 2 to 10 minutes prior to taking the tissue sample,
- whereby the blood sample is taken directly prior to the tissue sample.
Claim 2 encompasses the method according to claim 1, wherein the tissue is either brain tissue and the therapeutic antibody can cross the blood-brain-barrier or any ocular tissue and the therapeutic antibody can cross the blood-ocular-barrier.
Claim 3 encompasses the method according claim 1, wherein the therapeutic antibody is any bispecific antibody.
Claim 4 encompasses the method according claim 1, wherein the therapeutic antibody is specifically binding to human transferrin receptor and any brain target.
Claim 5 encompasses the method according claim 1, wherein the brain target is selected from the group consisting of human CD20, human Abeta, human alpha-synuclein, human tau, human glucocerebrosidase, human lingo-1, and human huntingtin.
Claim 6 encompasses the method according claim 1, wherein the experimental animal is selected from mouse, rat, rabbit, dog, sheep, ape, and monkey.
Claim 7 encompasses the method according claim 1, wherein the experimental animal is a non-human experimental animal with a body weight of more than 100 g and less than 15 kg.
Claim 8 encompasses the method according claim 1, wherein the experimental animal is a cynomolgus monkey.
Claim 9 encompasses the method according claim 1, wherein the inert reference antibody is any human germline antibody.
Claim 10 encompasses the method according claim 1, wherein the inert reference antibody is DP47GS.
Claim 11 encompasses the method according claim 1, wherein the inert reference antibody does not cross said barrier in detectable amounts within 15 minutes after its application.
Claim 12 encompasses the method according claim 11, wherein the inert reference antibody does not cross said barrier in detectable amounts within 10 minutes after its application.
Claim 13 encompasses the method according claim 1, wherein the inert antibody is administered about 5 minutes prior to taking the tissue sample.
Claim 14 encompasses the method according claim 1, wherein the tissue is perfused with an aqueous solution directly after taking the blood sample and prior to taking the tissue sample.
Claim 15 encompasses the method according claim 1, wherein the determining of the concentrations is by a bridging ELISA.
Claim 16 encompasses the method according to claim 5, wherein the experimental animal is selected from the group consisting of mouse, rat, rabbit, dog, sheep, ape, and monkey.
Claim 17 encompasses the method according to claim 16, wherein the experimental animal is a non-human experimental animal with a body weight of more than 100 g and less than 15 kg.
Claim 18 encompasses the method according to claim 16, wherein the experimental animal is a cynomolgus monkey.
Claim 19 encompasses the method according to claim 5, wherein the inert reference antibody is a human germline antibody.
Claim 20 encompasses the method according to claim 16, wherein the inert reference antibody is a human germline antibody.
Regarding tissue that has a barrier to the blood circulation of any experimental animal, the specification discloses a method of determining the amount of therapeutic antibody in residual blood in a brain lysate of cynomolgus monkey. The method comprises (A) administering to the monkey a therapeutic antibody, (B) administering a reference antibody DP47GS that does not diffuse during the perfusion phase into the brain, wherein the reference antibody comprising a heavy chain variable region and a light chain variable region wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 67 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 68, wherein the reference antibody is administered within 5 minutes after administering the therapeutic antibody or two to ten minutes prior to perfusion and taking tissue sample, (C) determining the concentration of therapeutic antibody in a blood sample using ELISA, (D) determining the concentration of the therapeutic antibody in the brain tissue sample using ELISA, (E) determining the determining the concentration of reference antibody in a blood sample using ELISA, (F) determining the determining the concentration of reference antibody in a brain tissue sample using ELISA and (G) calculating the concentration of the therapeutic antibody in the brain tissue of the monkey with the formula:
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Regarding therapeutic antibody is any bispecific antibody (claim 3), such as any bispecific antibody that binds to human transferrin receptor and any brain target (claim 4), any brain target such as human CD20, human Abeta, human alpha-synuclein, human tau, human glucocerebrosidase, human lingo-1, and human huntingtin (claim 5), the specification defines the “brain target” as follow:
[0120] The terms “CNS antigen” and “brain target” denote an antigen and/or molecule expressed in the CNS, including the brain, which can be targeted with an antibody or small molecule. Examples of such antigen and/or molecule include, without limitation: beta-secretase 1 (BACE1), amyloid beta (Abeta), epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), Tau, apolipoprotein E4 (ApoE4), alpha-synuclein, CD20, huntingtin, prion protein (PrP), leucine rich repeat kinase 2 (LRRK2), parkin, presenilin 1, presenilin 2, gamma secretase, death receptor 6 (DR6), amyloid precursor protein (APP), p75 neurotrophin receptor (p75NTR), glucocerebrosidase and caspase 6.
Thus, the brain targets to which the bispecific therapeutic bind, are unlimited.
The specification discloses:
A. Exemplary Bispecific Antibody: Anti-Human A-Beta/Human Transferrin Receptor Antibody
[0208] In certain embodiments, the therapeutic antibody to be determined in a method according to the current invention is an antibody that binds to human A-beta and human transferrin receptor.
[0209] Exemplary antibody 0012 is composed of four polypeptides that have the amino acid sequence of SEQ ID NO: 04 to 07.
[0210] Exemplary antibody 0015 is composed of four polypeptides that have the amino acid sequence of SEQ ID NO: 08 to 11.
[0211] Exemplary antibody 0020 is composed of three polypeptides that have the amino acid sequence of SEQ ID NO: 12 to 14.
[0212] Exemplary antibody 0024 is composed of four polypeptides that have the amino acid sequence of SEQ ID NO: 15 to 18.
[0231] In one embodiment, the human A-beta binding site comprises the VH sequence as in SEQ ID NO: 19, including post-translational modifications of that sequence and the VL sequence as in SEQ ID NO: 20.
[0232] In one embodiment, the human transferrin receptor-binding site comprises the VH sequence as in SEQ ID NO: 21, including post-translational modifications of that sequence and the VL sequence as in SEQ ID NO: 22.
B. Exemplary Anti-Transferrin Receptor Antibodies
[0266] The anti-transferrin receptor binding site of a therapeutic antibody to be determined in a method according to the current invention have an off-rate for binding to the human transferrin receptor that is within a certain range in order to ensure proper BBB shuttling. This range is defined at the one end by the off-rate of the murine anti-transferrin receptor antibody 128.1 (variable domain amino acid sequences given in SEQ ID NO: 27 and 28)
[0267] One aspect as reported herein is an anti-transferrin receptor antibody that specifically binds to human transferrin receptor and cynomolgus transferrin receptor, which comprises
[0268] i) a humanized heavy chain variable domain derived from the heavy chain variable domain of SEQ ID NO: 29, and
[0269] ii) a humanized light chain variable domain derived from the light chain variable domain of SEQ ID NO: 30,
[0270] wherein the antibody has an off-rate for the human transferrin receptor that is equal to or less than (i.e. at most) the off-rate of the anti-transferrin receptor antibody 128.1 for the cynomolgus transferrin receptor,
[0271] whereby the off-rates are determined by surface plasmon resonance, and
[0272] whereby the anti-transferrin receptor antibody 128.1 has a heavy chain variable domain of SEQ ID NO: 27 and a light chain variable domain of SEQ ID NO: 28.
[0284] In one embodiment, the anti-transferrin receptor binding site of the therapeutic antibody comprises the heavy chain variable domain of SEQ ID NO: 31 and the light chain variable domain of SEQ ID NO: 32 which reflect with respect to the human transferrin receptor the binding properties of the murine antibody 128.1 with respect to the cynomolgus transferrin receptor regarding the binding off-rate.
[0285] In one embodiment, the anti-transferrin receptor binding site of the therapeutic antibody specifically binds to human transferrin receptor (huTfR) and cynomolgus transferrin receptor (cyTfR) and comprises i) a humanized heavy chain variable domain derived from the heavy chain variable domain of SEQ ID NO: 29 and ii) a humanized light chain variable domain derived from the light chain variable domain of SEQ ID NO: 30, wherein the light chain variable domain has at position 80 a proline amino acid residue (P), at position 91 an asparagine amino acid residue (N) and at position 93 an alanine amino acid residue (A) (numbering according to Kabat).
[0293] In one embodiment, the antibody is a bispecific antibody comprising at least one pair of a heavy chain variable domain of SEQ ID NO: 31 and a light chain variable domain of SEQ ID NO: 32 forming a binding site for the transferrin receptor and at least one pair of a heavy chain variable domain of SEQ ID NO: 41 and a light chain variable domain of SEQ ID NO: 42 binding site for human CD20.
[0294] In one embodiment, the antibody is a bispecific antibody comprising at least one pair of a heavy chain variable domain of SEQ ID NO: 31 and a light chain variable domain of SEQ ID NO: 32 forming a binding site for the transferrin receptor and at least one pair of a heavy chain variable domain of SEQ ID NO: 43 and a light chain variable domain of SEQ ID NO: 44 binding site for human alpha-synuclein.
[0295] In one embodiment, the antibody is a bispecific antibody comprising at least one pair of a heavy chain variable domain of SEQ ID NO: 31 and a light chain variable domain of SEQ ID NO: 32 forming a binding site for the transferrin receptor and at least one pair of a humanized heavy chain variable domain derived from SEQ ID NO: 45 and a humanized light chain variable domain derived from SEQ ID NO: 46 binding site for human alpha-synuclein.
[0296] In one embodiment, the antibody is a bispecific antibody comprising at least one pair of a heavy chain variable domain of SEQ ID NO: 31 and a light chain variable domain of SEQ ID NO: 32 forming a binding site for the transferrin receptor and at least one pair of a humanized heavy chain variable domain derived from SEQ ID NO: 47 and a humanized light chain variable domain derived from SEQ ID NO: 48 binding site for human alpha-synuclein.
[0297] In one embodiment, the antibody is a bispecific antibody comprising at least one pair of a heavy chain variable domain of SEQ ID NO: 31 and a light chain variable domain of SEQ ID NO: 32 forming a binding site for the transferrin receptor and at least one pair of a humanized heavy chain variable domain derived from SEQ ID NO: 49 and a humanized light chain variable domain derived from SEQ ID NO: 50 binding site for human alpha-synuclein.
[0298] In one embodiment, the antibody is a bispecific antibody comprising at least one pair of a heavy chain variable domain of SEQ ID NO: 31 and a light chain variable domain of SEQ ID NO: 32 forming a binding site for the transferrin receptor and at least one pair of a humanized heavy chain variable domain derived from SEQ ID NO: 51 and a humanized light chain variable domain derived from SEQ ID NO: 52 binding site for human alpha-synuclein.
[0299] In one embodiment, the antibody is a bispecific antibody comprising at least one pair of a heavy chain variable domain of SEQ ID NO: 31 and a light chain variable domain of SEQ ID NO: 32 forming a binding site for the transferrin receptor and at least one pair of a humanized heavy chain variable domain derived from SEQ ID NO: 53 and a humanized light chain variable domain derived from SEQ ID NO: 54 binding site for human alpha-synuclein.
[0300] In one embodiment, the antibody is a bispecific antibody comprising at least one pair of a heavy chain variable domain of SEQ ID NO: 31 and a light chain variable domain of SEQ ID NO: 32 forming a binding site for the transferrin receptor and a binding site for i) glucocerebrosidase that has the amino acid sequence of SEQ ID NO: 55 or ii) a functional variant of SEQ ID NO: 55 having at least 70% sequence identity, or iii) a functional variant of SEQ ID NO: 55 having one or more amino acid mutations, deletions or insertions, or iv) a truncated functional variant of SEQ ID NO: 55 having at least one amino acid residue at the N-terminus or the C-terminus or within the amino acid sequence deleted, or v) a combination of iii) and iv).
However, the specification does not describe the structure, e.g., amino acid sequence of the heavy and light chain variable regions about the corresponding makeup of the genus of bispecific antibodies (claim 3) that correlated with binding human transferrin receptor and any brain target (claim 4), any brain target such as human tau, human glucocerebrosidase (elected species), human lingo-1, and human huntingtin (claim 5) encompassed by the claimed method. The specification does not describe a representative number of species falling within the scope of the genus of bispecific antibodies or structural features common to the members of the genus so the one of skill in the art can visualize or recognize the member of the genus of the actual antibody in the claimed method.
In Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), the court explained in Amgen that when an antibody is claimed, 35 U.S.C § 112(a) requires adequate written description of the antibody itself. Thus one of skill in the art cannot "visualize or recognize" most members of the genus.
As in Amgen, the pending claims of the instant case attempt to describe a genus of antibodies by describing something that is not an antibody, i.e. the antigen to which the antibody binds (claims 4, 5). Also analogous to Amgen, the fact that antigenic structures are known in detail would enable one of skill in the art to make antibodies meeting the binding limitations of the claims. As noted in Amgen, however, this is not enough to meet the written description requirement.
“When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus.” See Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005).
Regarding the reference human germline antibody (claims 9, 19, 20), the specification discloses just one DP47GS antibody comprising a heavy chain variable region and a light chain variable region wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 67 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 68.
However, one species is not representative of the genus of human germline antibodies. An adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
The specification does not describe a representative number of species falling within the scope of the genus or structural features common to the members of the genus so the one of skill in the art can visualize or recognize the member of the genus of the actual claimed human germline antibody encompassed by the claimed method.
At the time the invention was made, it was known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. Protein Engineering, Design & Selection 22:159-168, 2009; PTO 1449; see, e.g., Discussion).
Similarly, Edwards et al (J Mol Biol 14;334(1): 103-118, 2003; PTO 1449) found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Goel et al (J. Immunol 173: 7358-7367, 2004; PTO 892) teach that three mAbs that bind to the same short (12-mer) peptide, exhibit diverse V gene usage, indicating their independent germline origin. Said reference further teaches that two of these mAbs recognize the same set of amino acid residues defining the epitope (alternate amino acid residues spread over the entire sequence), however, the relative contribution of each set of residues in the peptide showed significant variation. The said reference notes that all of the mAbs do not show any kind of V gene restriction among themselves, implying variable paratope structure, despite that two of these mAbs bind to the peptide through a common set of residues. (See entire reference).
Khan and Salunke (J. Immunol 192: 5398-5405, 2014; PTO 892) teach that two structurally diverse germline mAbs recognizing overlapping epitopes of the same short peptide do so in different topologies, the said antibodies possessing entirely different CDR sequences.
Poosarla et al (Biotechn. Bioeng., 114(6): 1331-1342, 2017; PTO 892) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
Given that hundreds of unique antibody structures may bind a single antigen, the structure of an antibody cannot be predicted from the structure of the antigen (as held in Amgen), and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen (as held in Abbvie).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “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).
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddles v. Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Thus, it appears that the instant specification does not adequately disclose the breadth of the human germline antibody, therapeutic antibody or bispecific antibody that binds to human transferrin receptor and any brain target such as any human tau, or human glucocerebrosidase or human lingo-1 or human huntingtin in the claimed method recited in the instant claims. In light of this, a skilled artisan would reasonably conclude that Applicant was not in possession of the genus of all the said human germline antibody and bispecific antibody that binds to human transferrin receptor and any brain target such as any human tau, or human glucocerebrosidase or human lingo-1 or human huntingtin at the time the instant application was filed, and hence not in possession of the claimed method of using said antibody at the time the instant application was filed.
Therefore, only a method of determining the amount of therapeutic antibody in residual blood in a brain lysate of cynomolgus monkey, the method comprises (A) administering to the monkey a therapeutic antibody, (B) administering a reference antibody DP47GS that does not diffuse during the perfusion phase into the brain, wherein the reference antibody comprising a heavy chain variable region and a light chain variable region wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 67 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 68, wherein the reference antibody is administered within 5 minutes after administering the therapeutic antibody or two to ten minutes prior to perfusion and taking tissue sample, (i) determining the concentration of therapeutic antibody in a blood sample using ELISA, (ii) determining the concentration of the therapeutic antibody in the brain tissue sample using ELISA, (iii) determining the determining the concentration of reference antibody in a blood sample using ELISA, (iv) determining the determining the concentration of reference antibody in a brain tissue sample using ELISA and (v) calculating the concentration of the therapeutic antibody in the brain tissue of the monkey with the formula:
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Wherein Ctm,Ab,plasma,det is the concentration of therapeutic antibody in the blood sample in (i),
Wherein CtmAb,tissue,det, is the concentration of the therapeutic antibody in the tissue sample in (ii),
Wherein CrefmAb,plasma,det is the concentration of reference antibody in the blood sample (iii),
Wherein CrefmAb,tissue,det is the concentration of reference antibody in the tissue sample in (iv),
Wherein Ctissue,sample is the tissue concentration of (v), but not the full breadth of the claims meets 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).
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 claims at issue 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); and 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 11,913,945. Although the claims at issue are not identical, they are not patentably distinct from each other because while the ‘945 patent issued from the application which served as the parent for the present case, the examined application was filed as a CON, not a DIV, and therefore no shield against double patenting that might be provided by 35 U.S.C 121 would be applicable here.
Issued claim 1. A method for determining the concentration of a therapeutic antibody in a tissue of an experimental animal, whereby the tissue has a barrier to the blood circulation of said animal and whereby the therapeutic antibody had been administered to said experimental animal, wherein the interference from residual blood in a tissue sample of the experimental animal, which is used for determining the concentration of the therapeutic antibody in said tissue, is reduced, the method comprising the following steps of administering a therapeutic antibody and an inert reference antibody to the experimental animal,
determining the concentration of the therapeutic antibody in a blood sample of the experimental animal,
determining the concentration of the therapeutic antibody in the tissue sample of the experimental animal,
determining the concentration of an inert reference antibody in the blood sample of the experimental animal,
determining the concentration of the inert reference antibody in the tissue sample of the experimental animal,
determining the tissue concentration in the tissue sample, and determining the concentration of the therapeutic antibody in the tissue of the experimental animal with the following formula:
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whereby the blood sample is taken directly prior to the tissue sample,
wherein the inert reference antibody is DP47GS, wherein the inert reference antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 67 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 68, which corresponds to instant claims 1 and 10.
The reference SEQ ID NO: 67 is identical to the claimed SEQ ID NO: 67, see sequence alignment below:
OTHER INFORMATION: DP47GS VH
Query Match 100.0%; Score 599; Length 115;
Best Local Similarity 100.0%;
Matches 115; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYY 60
Qy 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGSGFDYWGQGTLVTVSS 115
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGSGFDYWGQGTLVTVSS 115
The reference SEQ ID NO: 68 is identical to the claimed SEQ ID NO: 68, see sequence alignment below:
OTHER INFORMATION: DP47 light chain
Query Match 100.0%; Score 555; Length 215;
Best Local Similarity 100.0%;
Matches 108; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIP 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIP 60
Qy 61 DRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPLTFGQGTKVEIK 108
||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPLTFGQGTKVEIK 108
2. The method according to claim 1, wherein the tissue is either brain tissue and the therapeutic antibody can cross the blood-brain-barrier or ocular tissue and the therapeutic antibody can cross the blood-ocular-barrier, which corresponds to instant claim 2.
3. The method according to claim 1, wherein the therapeutic antibody is a bispecific antibody, which corresponds to instant claim 3.
4. The method according to claim 1, wherein the therapeutic antibody is specifically binding to human transferrin receptor and a brain target, which corresponds to instant claim 4.
5. The method according to claim 4, wherein the brain target is selected from the group consisting of human CD20, human Abeta, human alpha-synuclein, human tau, human glucocerebrosidase, human lingo-1, and human huntingtin, which corresponds to instant claim 5.
6. The method according to claim 1, wherein the experimental animal is selected from mouse, rat, rabbit, dog, sheep, ape, and monkey, which corresponds to instant claims 6, 16.
7. The method according to claim 1, wherein the experimental animal is a non-human experimental animal with a body weight of more than 100 g and less than 15 kg, which corresponds to instant claims 7, 17.
8. The method according to claim 1, wherein the experimental animal is a cynomolgus monkey, which corresponds to instant claims 8, 18.
9. The method according to claim 1, wherein the inert reference antibody is a human germline antibody, which corresponds to instant claims 9, 19, 20.
10. The method according to claim 1, wherein the inert reference antibody does not cross said barrier in detectable amounts within 15 minutes after its application, which corresponds to instant claim 10.
11. The method according to claim 10, wherein the inert reference antibody does not cross said barrier in detectable amounts within 10 minutes after its application, which corresponds to instant claim 12.
12. The method according to claim 1, wherein the inert antibody is administered about 5 minutes prior to taking the tissue sample, which corresponds to instant claim 13.
13. The method according to claim 1, wherein the tissue is perfused with an aqueous solution directly after taking the blood sample and prior to taking the tissue sample, which corresponds to instant claim 14.
14. The method according to claim 1, wherein the determining of the concentrations is by a bridging ELISA, which corresponds to instant claim 15.
A person of skill in the art, reading the claims of the ‘945 patent, would look to the patent and follow the ‘945 patent’s express instruction on how to determine the concentration of a therapeutic antibody in a tissue of an experimental animal within the patent, e.g., Examples thereby arriving at the method of the examined claims.
Species Restriction Withdrawn
Upon reconsideration, the species restriction is hereby withdrawn.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHUONG HUYNH whose telephone number is (571)272-0846. The examiner can normally be reached on 9:00 a.m. to 6:30 p.m. The examiner can also be reached on alternate alternative Friday from 9:00 a.m. to 5:30 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Misook Yu, can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PHUONG HUYNH/ Primary Examiner, Art Unit 1641
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