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 .
Formal Matters
Applicant’s response in the reply filed on 18 September 2025 is acknowledged and has been fully considered. Claims 3-5, 16-20, and 28-31 are pending. Claims 3-5 and 20 are under consideration in the instant office action. Claims 16-19 and 28-31 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species, there being no allowable generic or linking claim. Claims 1-2, 6-15, and 21-27 are canceled.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 3, now claim 4 by amendment, and 5) drawn to an anti-TfR antibody or antigen-binding fragment in the reply filed on 18 September 2025 is acknowledged. Additionally, Applicant’s election without traverse of a species an anti-TfR antibody or antigen-binding fragment thereof having the complementarity-determining regions (CDRs) of SEQ ID NOs: 292, 293, 294, 295, 296,and 297 in the reply filed on 18 September 2025 is also acknowledged. Upon further consideration by the examiner, the restriction requirement on Group II (claim 4 now depending from claim 3), Group III (now cancelled claim 6), Group IV (now canceled claims 7-11) and Group IX (claim 20) are hereby withdrawn. Claims 4 and 20 are examined along with claims 3 and 5 on the merits.
NOTE: the restriction among all other groups (Groups V, VI, VII, VIII, X, XI, XII and XIII) is maintained.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 18 September 2025, 25 February 2025, and 09 March 2023 are noted and the submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the examiner has considered the references. Signed copies are attached herein.
Claim Rejections - 35 USC § 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.
Claim 4 is 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
This is a “written description” rejection.
The considerations that are made in determining whether a claimed invention is supported by an adequate written description are outlined by the published Guidelines for Examination of Patent Applications Under the 35 U.S.C. 112, para. 1, ``Written Description'' Requirement (Federal Register; Vol. 66, No. 4, January 5, 2001; hereinafter “Guidelines”). A copy of this publication can be viewed or acquired on the Internet at the following address: <http://www.gpoaccess.gov/>.
These guidelines state that rejection of a claim for lack of written description, where the claim recites the language of an original claim should be rare. Nevertheless, these guidelines further state, “the issue of a lack of written description may arise even for an original claim when an aspect of the claimed invention has not been described with sufficient particularity such that one skilled in the art would recognize that the applicant has possession of the claimed invention” (Id. at 1105). The “Guidelines” continue:
The claimed invention as a whole may not be adequately described if the claims require an essential or critical feature which is not adequately described in the specification and which is not conventional in the art or known to one of ordinary skill in the art. This problem may arise where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function. A lack of adequate written description issue also arises if the knowledge and level of skill in the art would not permit one skilled in the art to immediately envisage the product claimed from the disclosed process.
Furthermore, the Federal Circuit has commented that each case involving the issue of written description, “must be decided on its own facts. Thus, the precedential value of cases in this area is extremely limited.” Vas-Cath, 935 F.2d at 1562 (quoting In re Driscoll, 562 F.2d 1245, 1250 (C.C.P.A. 1977)). See Noelle v. Lederman, 69 USPQ2d 1508 (CAFC 2004).
Finally, with further regard to the proposition that, as original claims, the claims themselves provide in haec verba support themselves provide in haec verba support sufficient to satisfy the written description requirement, the Federal Circuit has explained that in ipsis verbis support for the claims in the specification does not per se establish compliance with the written description requirement:
Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement. The disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described. Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997). See also: University of Rochester v. G.D. Searle & Co., 69 USPQ2d 1886 1892 (CA FC 2004).
Thus, an original claim may provide written description for itself, but it must still be an adequate written description, which establishes that the inventor was in possession of the invention.
In the instant case, claim 3 is drawn to “An anti-transferrin receptor (TfR) antibody or antigen-binding fragment thereof comprising: a heavy chain variable region comprising heavy chain complementarity determining regions (HCDRs) HCDR1, HCDR2 and HCDR3, and a light chain variable region comprising light chain complementarity determining regions (LCDRs) LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 292, 293, 294, 295, 296, and 297, respectively.” Instant claim 4, which depends from claim 3 recites “The anti-TfR antibody or antigen-binding fragment thereof of claim 3, comprising a single-chain variable fragment (scFv) comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 291 or 162.”
However, the genus of single chain variable fragment sequences having at least 90% sequence identity to the variable region sequences of SEQ ID NOs: 291 or 162, as recited in claim 4, which encompasses amino acid changes including substitutions, and deletions in the heavy chain complementarity determining regions (HCDRs) HCDR1, HCDR2, HCDR3 and light chain complementarity determining regions (LCDRs) LCDR1, LCDR2, and LCDR3. A single chain variable fragment sequence having at least 90% sequence identity to SEQ ID NOs: 291 or 162 encompasses sequences with up to 10% variation from SEQ ID NO:291 or 162, and such variations could occur within one or more of the CDR regions. The specification as filed does not demonstrate that the inventor had possession of the full scope of the claimed genus of single chain variable region sequences having at least 90% sequence identity to SEQ ID NO:291 or 162. The species of single chain variable fragments having SEQ ID Nos: 291 or 162 does not support the claim to the genus of single chain variable fragments with up to 10% variation therefrom. The specification does not provide guidance as to which additions substitutions or deletions at what points in the single chain variable fragment to make. The specification does not provide representative examples, a structure-function correlation, or other evidence showing possession of variants that retain the binding function to the transferring receptor. See Ariad Pharm., Inc. V. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir.2010) (en banc) (requiring that the specification “reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the effective filing date”); see also AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc., 759 F.3d 1285, 1299-1300 (Fed. Cir. 2014) (finding lack of written description where the claimed genus encompassed functionally defined antibodies but the specification disclosed only a limited number of structurally similar examples without sufficient representation of the broader structural diversity).
With respect to claim 4 reciting “The anti-TfR antibody or antigen-binding fragment thereof of claim 3, comprising a single-chain variable fragment (scFv) comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 291 or 162.” which do not necessarily comprise the three CDRs from the light chain variable region and the three CDRs from the heavy chain variable region from a parental antibody in the proper context of light and heavy chain variable regions, it is submitted that the specification has not adequately described such “antibodies” because the art recognizes that the antigen-combining site of a conventional antibody requires six “complementarity-determining regions” (CDRs), three each from the light and heavy chains to specifically bind antigen. Therefore, one of skill in the art could not immediately envision, recognize or predict the structure of “antibodies” which need not have all the CDRs of the parental antibody in the proper context of heavy and light chain regions.
To elaborate on why the claimed antibodies lack adequate written description, Mariuzza et al. (Annu. Rev. Biophys. Biophys. Chem. 1987; 16: 139-159) reviews the structural basis of antigen-antibody recognition and teaches that naturally occurring conventional antibodies comprise two polypeptides, the so-called light and heavy chains. The antigen-combining site of an antibody is a three-dimensional structure, which fully comprises six “complementarity-determining regions” (CDRs), three each from the light and heavy chains. The amino acid sequences of the CDRs are hypervariable, as the amino acid residues contained within the CDRs determine much of antibody's antigen-binding specificity.
In view of Mariuzza et al., it is apparent that antibodies having less than all six CDRs that form the antigen binding site of a conventional antibody in their proper context of heavy and light chain variable domains do not describe the particularly identifying structural feature of the parental antibody that correlates with the antibody's ability to bind to the antigen. Absent a description of the at least minimal structural features correlating with a functional ability to bind to a particular antigen, which are shared by members of a genus commonly sharing this function, it is submitted that the skilled artisan could not immediately envision, recognize or distinguish antibodies comprising CDRs replaced from the parental antibody that bind the transferrin receptor from those comprising CDRs replaced from the parental antibody that do not bind the transferrin receptor. For these reasons, the specification would not reasonably convey to the skilled artisan that Applicant had possession of the claimed invention at the time the application was filed.
While the prior art teaches well-known and conventional methodology for CDR grafting heavy and light chain CDRs into corresponding heavy and light chain frameworks to give an antibody that binds the same antigen as the parent antibody, one of skill in the art would not immediately envision or recognize antibodies or fragments thereof comprising less than all 6 CDRs of a parent antibody which are not in the proper context of heavy and light chain frameworks as retaining the binding affinity and specificity of the parent antibody.
For example, Gussow et al. (Methods in Enzymology. 1991; 203: 99-121) teach the general methodology for making CDR grafted antibodies that retain the antigen-binding function of the parental antibody; see entire document. One means for producing a CDR grafted antibody that retains the antigen-binding function of the parental antibody involves grafting the six CDRs from the light and heavy chain variable regions from a murine antibody into the framework of a human antibody. However, in general, if only the CDRs from the light and heavy chain variable region were included without being in the proper context of the framework of an antibody or if only a fragment with less than all 6 CDRs grafted into the proper context of antibody light and heavy chain framework regions were included, the resultant antibody or fragment would not be expected to retain the binding specificity of the parent antibody. Therefore, since it is expected that all 6 CDRs need to be grafted into the proper context of heavy and light chain framework regions to retain the requisite specificity of the parent antibody and all 6 CDRs in their proper context of antibody frameworks need to be present in antigen-binding fragments, the claimed antibodies or fragments which need not contain all 6 CDRs of any described conventional parent antibody in the proper context of light and heavy chain variable regions, would not be immediately envisioned or recognized by one of skill in the art as having the specificity of the parent antibody.
Furthermore, while the prior art teaches some understanding of the structural basis of antigen-antibody recognition and conventional methodology for humanizing monoclonal antibodies, it is aptly noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains and surrounding framework regions of antibodies. For example, Giusti et al. (Proc. Natl. Acad. Sci. USA. 1987 May; 84 (9): 2926-2930) teaches the specificity and affinity of an antibody is exquisitely sensitive to amino acid substitutions within the primary structure of the antibody, since only a single amino acid substitution in the heavy chain of an antibody completely altered the binding specificity of an antibody that binds phosphocholine, such that the altered antibody fails to bind phosphocholine but instead binds DNA; see entire document (e.g., the abstract). This unpredictability of single amino acid changes in an antibody is underscored by Winkler et al (J. Imm., 265:4505-4514, 2000) who teach that single amino acid changes in antibody side chains can result in unpredictable and substantial changes in antibody specificity; see entire document (e.g., the abstract). Chien et al. (Proc. Natl. Acad. Sci. USA. 1989 Jul; 86 (14): 5532-5536) teaches that significant structural and functional changes in an antigen-binding site can be caused by amino acid substitutions in the primary structure of an antibody, including substitutions at a site remote from the complementarity determining regions of the antigen-binding domain; see entire document (e.g., the abstract). Similarly, but more recently, Caldas et al. (Mol. Immunol. 2003 May; 39 (15): 941-952) teaches an unexpected effect of substituting a framework residue upon binding specificity during the humanization of an antibody that binds CD18; see entire document (e.g., the abstract).
The Federal Circuit has decided that a patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated. See Noelle v. Lederman, 69 USPQ2d 1508 1514 (CA FC 2004) (citing Enzo Biochem II, 323 F.3d at 965; Regents, 119 F.3d at 1568).
Additionally, “generalized language may not suffice if it does not convey the detailed identity of an invention.” University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1892 (CAFC 2004).
The purpose of the “written description” requirement is broader than to merely explain how to “make and use”; the 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.
Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (CAFC 1991). See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993); Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (CAFC 1991); University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1892 (CAFC 2004).
“Guidelines” states, “[p]ossession may be shown in a variety of ways including description of an actual reduction to practice, or by showing the invention was 'ready for patenting' such as by disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention” (Id. at 1104). Moreover, because the claims are directed to a genus of structurally disparate “antibodies, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. In this instance, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; Applicant has not shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; and Applicant has not described distinguishing identifying characteristics sufficient to show that Applicant was in possession of the claimed invention at the time the application was filed.
Once again the specification does not characterize species representative of the claimed genus as it does not characterize all CDR residues that are required to maintain specific binding to transferrin receptor. Notably, as the specification does not characterize all CDR residues that can be varied the described species are not representative of the genus of claimed antibodies. Accordingly, one of skill in the art would not be able to immediately envision, recognize or predict the structure of antibodies comprising less than all 6 of the recited CDRs in the proper context of heavy and light chain frameworks which would have the function of binding to transferrin receptor and would not recognize that Applicant was in possession of the claimed invention. While it is noted that the specification does identify multiple species of antibodies that bind transferrin receptor, it does not identify which CDRs are not required for binding or that all CDRs can be swapped one for the other. Therefore, it is apparent that the disclosed species are not representative of the claimed antibodies that only give partial CDR structure.
Given the lack of particularity with which the antibodies are described in the specification, it is submitted that the skilled artisan could not immediately envision, recognize or distinguish at least most of the members of the claimed genera, to which the claims are directed; and therefore the specification would not reasonably convey to the skilled artisan that Applicant had possession of the claimed invention at the time the application was filed.
It is suggested that this rejection could be overcome by amending claim 4 to recite:a single chain antibody (scFv) comprising the amino acid sequence of SEQ ID NO:291 or 162.
Claim 4 is 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 making and using antibodies that specifically bind transferrin receptor (TfR), wherein said antibodies comprise a single-chain antibody (scFv) comprising the amino acid sequence of SEQ ID NO: 291 or 162 and compositions thereof, does not reasonably provide enablement for making and using the full scope of antibodies encompassed by the claims, such as anti -TfR antibodies comprising a single-chain variable fragment (scFv) comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 291 or 162.” and compositions comprising such.
MPEP § 2164.01 states:
The standard for determining whether the specification meets the enablement requirement was cast in the Supreme Court decision of Mineral Separation v. Hyde, 242 U.S. 261, 270 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? That standard is still the one to be applied. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though the statute does not use the term "undue experimentation," it has been interpreted to require that the claimed invention be enabled so that any person skilled in the art can make and use the invention without undue experimentation. In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988).
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue”. These factors, which have been outlined in the Federal Circuit decision of In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), include, but are not limited to, the nature of the invention, the state of the prior art, the relative skill of those in the art, the amount of direction or guidance disclosed in the specification, the presence or absence of working examples, the predictability or unpredictability of the art, the breadth of the claims, and the quantity of experimentation which would be required in order to practice the invention as claimed. See also Ex parte Forman, 230 USPQ 546 (BPAI 1986).
The scope of claim 4 is described supra.
In this case, the specification only provides specific, non-general guidance on how to make and use antibodies encompassed by the claims antibodies that specifically bind TfR. The species of single chain antibodies having SEQ ID Nos: 291 or 162 does not provide adequate guidance for one of ordinary skill in the art how to make and use single chain variable fragments comprising at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 291 or 162. This means the single chain antibody may have up to 10% variation therefrom. The specification does not provide guidance as to which additions substitutions or deletions at what points in the single chain antibody to make. There is no guidance regarding which variations will or will not retain binding specificity for transferrin receptor. One of ordinary skill in the art would be left to determine which amino acids may successfully be changed without any direction from the instant specification.
As evidenced by Mariuzza et al (supra), Gussow et al (supra), Giusti et al (supra) Chien et al (supra), Caldas et al (supra) and Winkler et al (supra), the state of the prior art is characterized by a high level of unpredictability, since the skilled artisan cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains and the state of the prior art indicates that grafting all 6 heavy and light chain CDRs into appropriate antibody framework results in antibodies retaining the binding affinity and specificity of the parent antibody. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al (Proc. Natl. Acad. Sci. USA 1982 Vol. 79: page 1979-1983). Rudikoff et al teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function. It is unlikely that antibodies that do not contain all of the 6 CDRs of the parent monoclonal antibody in their proper context of heavy and light chain variable domains, respectively, would retain the epitope-binding function of the parent antibody.
Thus, while the prior art teaches some understanding of the structural basis of antigen-antibody recognition and conventional methodology for humanizing monoclonal antibodies, it is aptly noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains and surrounding framework regions of antibodies.
The art of engineering functional recombinant antibodies, such as those to which the claims are directed, is even more confounded by findings that residues, which are positioned outside the recognized boundaries of the canonical CDRs, may contribute substantially to the interaction of an antibody and an antigen. For example, MacCallum et al. (J. Mol. Biol. 1996 Oct 11; 262 (5): 732-745) describes the discovery that although the residues of CDR3 of the heavy and light chains are dominant determinants of the interaction, a number of essential residues contacting the antigen have been placed outside the regions that are recognized using the conventional or standard definitions of the CDRs, which are generally used to define the components of the antigen binding site of the antibody; see entire document (e.g., page 733, column 2). Moreover, MacCallum et al. teaches an appreciation of the fact that residues within the CDRs that do not actually make contact with the antigen may be important because of their contributions to the conformation of the antibody’s antigen recognition site; see, e.g., page 735, column 1.
Making further apparent the unpredictability of the importance of residues within the CDRs and other parts of an antibody, which must instead be determined empirically, Holm et al. (Mol. Immunol. 2007 Feb; 44 (6): 1075-1084) describes the mapping of residues important to the interaction of an anti-cytokeratin antibody with the antigen, where although residues in the CDR3 of the heavy chain were determined to be essential, they disclose their unexpected finding that a residue in CDR2 of the light chain forms a necessary part of the antigen binding site of the antibody contacting the antigen; see entire document (e.g., the abstract). Thus, as recently as 2007, there are reports indicating despite the progress made toward understanding the interactions of antibodies and antigens, because of the unpredictable nature of the art, much information concerning the specificity and/or affinity of any given antibody cannot be gleaned by routine and conventional experimentation, but instead must be gathered by rigorous and undue experimentation. For these reasons, one of skill in the art would be subject to undue and unreasonable experimentation to make antibodies commensurate in scope with the claimed antibodies .
In this case, the specification lacks sufficient guidance as to the CDR amino acids that could be predictably altered while retaining the binding specificity of the parent antibody comprising a heavy chain variable region comprising CDRs 1, 2, and 3 which comprise the amino acid sequences of SEQ ID NOs: 292, 293, and 294, respectively and a light chain variable region comprising CDRs 1, 2, and 3 which comprise the amino acid sequences of SEQ ID NOs: 295, 296 and 297, respectively, such that one of skill in the art would be subject to undue and unreasonable experimentation to make antibodies commensurate in scope with the claimed antibodies.
Accordingly, in view of the state of the prior art, the amount of direction or guidance disclosed in the specification, the presence or absence of working examples, the unpredictability of the art and the broad breadth of the claims, one of skill in the art would be subject to undue and unreasonable experimentation to make and use antibodies commensurate in scope with the claimed antibodies.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 4 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Base claim 3 is drawn to “An anti-transferrin receptor (TfR) antibody or antigen-binding fragment thereof comprising: a heavy chain variable region comprising heavy chain complementarity determining regions (HCDRs) HCDR1, HCDR2 and HCDR3, and a light chain variable region comprising light chain complementarity determining regions (LCDRs) LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 292, 293, 294, 295, 296, and 297, respectively.” Instant claim 4, which depends from claim 3 recites “The anti-TfR antibody or antigen-binding fragment thereof of claim 3, comprising a single-chain variable fragment (scFv) comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 291 or 162.”. SEQ ID Nos: 291 and 162 are inclusive to the CDRs of base claim 3, however, the genus of single chain variable fragment sequences having at least 90% sequence identity to SEQ ID NOs: 291 or 162, as recited in claim 4, encompasses sequence variability and does not necessarily comprise the specific heavy chain complementarity determining regions (HCDRs) HCDR1, HCDR2, HCDR3 having the amino acid sequences of SEQ ID Nos: 292, 293, and 294, respectively, and light chain complementarity determining regions (LCDRs) LCDR1, LCDR2, and LCDR3 having an amino acid sequences of SEQ ID NOs: 295, 296, and 297, respectively as required by claim 3. A single chain variable fragment sequence having at least 90% sequence identity to SEQ ID NOs: 291 or 162 encompasses sequences with up to 10% variation from SEQ ID NOs:291 or 162, and such variations could occur within one or more of the CDRS regions, thereby resulting in CDR sequences that differ from and therefore omit those specifically recited and required in base claim 3. For example, prior art that teaches a sequence that is 95% identical to SEQ ID NO: 291 and includes at least one amino acid change in HCDR1 (SEQ ID NO:292) could conceivably infringe claim 4 without infringing claim 3. That is, claim 4, as written, broadens the scope of claim 3 by omitting required limitations of the CDRs since claim 4 more broadly defines the sequences and encompasses changes in the CDRs required by claim 3. Therefore, instant claim 4 does not further limit instant claim 3. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Double Patenting Rejections
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.
Claims 3-5 and 20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of copending Application No. 19/334,516 (hereinafter ‘516) in view of DENGL et al. (WO 2016/207240).
This is a provisional nonstatutory double patenting rejection.
Instant claim 3 recites “An anti-transferrin receptor (TfR) antibody or antigen-binding fragment thereof comprising: a heavy chain variable region comprising heavy chain complementarity determining regions (HCDRs) HCDR1, HCDR2 and HCDR3, and a light chain variable region comprising light chain complementarity determining regions (LCDRs) LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 292, 293, 294, 295, 296, and 297, respectively.” Instant claim 20 recites “A pharmaceutical composition comprising the anti-TfR antibody or antigen-binding fragment of claim 3 and a pharmaceutically acceptable carrier.”
‘516 recites in claim 1 “A conjugate comprising an anti-transferrin receptor (TfR) single-chain variable fragment (scFv) coupled to:
(i) a therapeutic or diagnostic agent; or
(ii) a second antibody that binds to a brain target;
wherein the anti-TfR scFv comprises a heavy chain variable region comprising heavy chain complementarity determining regions (HCDRs) HCDR1, HCDR2, and HCDR3 and a light chain variable region comprising light chain complementarity determining regions (LCDRs) LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 have the amino acid sequences of SEQ ID NOs: 292, 293, 294, 295, 296, and 297, respectively.”
Instant claims 3 and 20 differ from claim 1 of copending application ‘516 in that instant claim 3 does not have a therapeutic or diagnostic agent conjugated to the anti-transferrin receptor (anti-TfR) antibody or antigen-binding fragment thereof and a pharmaceutical composition comprising the anti-transferrin receptor (anti-TfR) antibody or antigen-binding fragment thereof and a pharmaceutically acceptable carrier. These deficiencies are cured by the teachings of DENGL et al. (WO2016207240).
DENGL et al. teach a humanized antibody that specifically binds to human transferrin receptor, wherein the antibody comprises in the heavy chain variable domain the HVRs of SEQ ID NO: 66, 68 and 72, and in the light chain variable domain the HVRs of SEQ ID NO: 75, 76 and 78 (see claim 1). DENGL et al. teach the term "monovalent binding entity" denotes a molecule able to bind specifically and in a monovalent binding mode to a BBBR. The blood brain shuttle module and/or conjugate as reported herein are characterized by the presence of a single unit of a monovalent binding entity i.e. the blood brain shuttle module and/or conjugate of the present invention comprise exactly one unit of the monovalent binding entity. The monovalent binding entity includes but is not limited to polypeptides, full length antibodies, antibody fragments including Fab, Fab', Fv fragments, single-chain antibody molecules such as e.g. single chain Fab, scFv. DENGL et al. teach a "conjugate" is fusion protein of the present invention conjugated to one or more heterologous molecule(s), including but not limited to a label, neurological disorder drug or cytotoxic agent (see page 25, lines 6-8). Furthermore, DENGL et al. also teach in another embodiment, a method of optimizing the pharmacokinetics and/or pharmacodynamics of a compound to be efficacious in the CNS in a subject is provided, wherein the compound is coupled to an antibody which binds with low affinity to TfR, and the antibody is selected such that its affinity for TfR after coupling to the compound results in an amount of transport of the antibody conjugated to the compound across the BBB that optimizes the pharmacokinetics and/or pharmacodynamics of the compound in the CNS (see page 51, lines 1-7). DENGL et al. teach pharmaceutical formulations of an anti-transferrin receptor antibody as described herein are prepared by mixing such antibody having the desired degree of purity with one or more optional pharmaceutically acceptable carriers (Remington's Pharmaceutical Sciences, 16th edition, Osol, A. (ed.) (1980)), in the form of lyophilized formulations or aqueous solutions. Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to: buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; etc., (see page 96, lines 10-35). Therefore, one of ordinary skill in the art would have recognized both the anti-transferrin receptor (anti-TfR) antibody or antigen-binding fragment thereof and a conjugate of said anti-transferrin receptor (anti-TfR) antibody or antigen-binding fragment thereof in the art as demonstrated by DENGL et al. along with preparing a pharmaceutical composition comprising anti-transferrin receptor (anti-TfR) antibody or antigen-binding fragment thereof wit a pharmaceutically acceptable carrier.
Instant claim 4, recites “The anti-TfR antibody or antigen-binding fragment thereof of claim 3, comprising a single-chain variable fragment (scFv) comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 291 or 162.” This corresponds to claim 2 of ‘516 which recites “The conjugate of claim 1, wherein the anti-TfR scFv is covalently linked to the second antibody or antigen binding fragment thereof.’516 in claim 3 recites “The conjugate of claim 1, wherein the anti-TfR scFv comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 291 or 162.”
Instant claim 5 recites “The anti-TfR antibody or antigen-binding fragment thereof of claim 3, comprising a single-chain variable fragment (scFv) comprising the heavy chain variable region covalently linked to the light chain variable region via a linker having the amino acid sequence of SEQ ID NO: 314.” This corresponds to claim 4 of ‘516 which recites “The conjugate of claim 1, wherein the heavy chain variable region is covalently linked to the light chain variable region via a linker having the amino acid sequence of SEQ ID NO: 314.”
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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/TIGABU KASSA/Primary Examiner, Art Unit 1619