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 .
Claim Status
The preliminary amendments filed on January 9, 2024 amended claims 20, 44-45, 48, 52, 53, 55, 57,58, 59, 61, 64, 83; canceled claims 2-16, 18-19, 22-24, 26-42, 46, 47, 50-51, 54, 56, 60, 62-63, 65-75, 77-82, 84-94, and added claims 95-160. Consequently claims 1, 17, 20, 21, 25, 43-45, 48-49, 52, 53, 55, 57-59, 61, 64,76, 83 and 95-160 are pending and will be examined on the merits.
Priority
The instant application claims benefit of a provisional application, Application No. 63393719 (filed 29 July, 2022). The effective filing date of instant claims 1-20 is 29 July, 2022.
Information Disclosure Statement
The information disclosure statement filed on July 13, 2023 comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, each information disclosure statement is being considered by the examiner.
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.
Claims 1, 55 and 83 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.
Claim 1 recites an antigen-binding protein that binds specifically to transferrin receptor or an antigenic-fragment thereof or variant thereof which comprises: (i) a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 2; 12; 22; 32; 42; 52; 62; 72; 82; 92; 102; 112; 122; 132; 142; 152; 162; 172; 182; 192; 202; 212; 222; 232; 242; 252; 262; 272; 282; 292; 302; or 312 (or a variant thereof); and/or (ii) a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 7; 17; 27; 37; 47; 57; 67; 77; 87; 97; 107; 117; 127; 137; 147; 157; 167; 177; 187; 197; 207; 217; 227; 237; 247; 257; 267; 277; 287; 297; 307; or 317 (or a variant thereof); which, optionally, is fused to a payload.
The use of parenthesis renders the claim indefinite because it is unclear whether the limitations included in the parenthesis are part of the claimed invention. See MPEP § 2173.05(d).
Claim 55 recites “a method for making the antigen-binding protein of claim 1, comprising culturing a host cell comprising a polynucleotide that encodes the fusion protein or antigen-binding protein in a culture medium under conditions favorable to expression of the fusion protein or antigen-binding protein.” There is a lack of antecedent basis for the polynucleotide that encodes the fusion protein and conditions favorable to expression of the fusion protein in the claim since the fusion protein is omitted in the amended claim.
Claim 83 recites a method of expressing in a cell a fusion protein comprising an antigen-binding protein that binds specifically to transferrin receptor or an antigenic-fragment thereof or variant thereof fused to a payload comprising: (a) administering to the cell a gene therapy vector comprising the isolated polynucleotide of claim 49, wherein the isolated polynucleotide encodes the fusion protein; (b) allowing the isolated polynucleotide to integrate into a genomic locus of the cell; and (c) allowing the cell to produce the fusion protein. However, claim 49 recites an isolated polynucleotide encoding the antigen-binding protein of claim 1, but not a fusion protein. Therefore, there is a lack of antecedent basis for the isolated polynucleotide that encodes the fusion protein in claim 83.
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.
Claims 1, 17, 20, 44, 45, 48, 49, 52, 53, 55, 57, 58, 59, 61, 64, 83, 95, 96, 97, 100, 102, 103, 106, 108, 109, 112, 114, 115, 118, 120, 121, 124, 126, 127, 128, 129, 132, 134, 135, 136, 137, 140, 141, 143, 144, 145, 148, 149, 151, 155, 158, and 160 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 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.
Claim 1 recites an antigen-binding protein that binds specifically to transferrin receptor or an antigenic-fragment thereof or variant thereof which comprises: (i) a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR comprising the amino acid sequence with indicated SED ID Nos (or a variant thereof); and/or (ii) a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR comprising the amino acid sequence with indicated SED ID Nos (or a variant thereof); which, optionally, is fused to a payload.
Claim 17 recites an antigen-binding protein that binds specifically to transferrin receptor or an antigenic-fragment thereof or variant thereof which binds to one or more epitopes of hTfR selected from 26 epitopes comprising or comprised within or overlapping with indicated sequences.
According to the specification of the instant application, “an antibody or antigen-binding fragment described herein may include conservative or non-conservative amino acid substitutions (referred to as "conservative variants" or "function conserved variants" of the antibody) that do not substantially alter its biologic activity” (page 36, column 1, paragraph [0140]), which provides interpretation of the "variant” of an antigen-binding protein that binds specifically to transferrin receptor or an antigenic-fragment thereof in claims 1 and 17 or the “variant” of an HVR or LVR of the antigen-binding protein in claim . However, the specification does not provide information regarding examples of these variants with specific sequences or structures. As such, these claims are drawn to a genus of antibodies with the function of being a transferrin receptor binding protein which the specification does not support.
In addition, claim 1 listed 32 HVR and 32 LVR sequences without specific pairing of these sequences. This would allow random pairing of these 32 HVR and 32 LVR sequences which represents a genus of antibodies that the specification does not describe or support.
Furthermore, claim 1 recites HCVR with listed sequences “and/or” LCVR with listed sequences, which allows proteins with only HCVRs or LCVRs with listed sequences, which are not described in the specification, and an ordinary artisan would not predict such proteins can function as TfR antibodies.
The applicants recite in Example 8, Hydrogen-Deuterium Exchange Mass Spectrometry (HDX-MS) was performed to delineate regions in mouse and human transferrin (m/hTfR) involved in binding of anti-Transferrin Receptor (TfR) antibodies in the instant invention. The minimal amino acid sequence in hTfR which is protected by the anti-TfR antibodies (i.e., the
minimal epitope sequence) are described in Table 8-3, which overlap with the amino acid sequences of the epitopes recited in claim 17. These epitopes identified by HDXMS experiments are assigned to 5 regions in TfR (PDB1SUV) as depicted in FIG. 13. Most of the epitopes have only 1-2 antibodies that can bind to them. For example, for the regions in the protease like domain of hTfR bound by the antibody H1H12799B, there is no other antibodies in the disclosure that binds to the same region (Fig. 13, Tables 8-3, 8-8, pages 183, 185). However, a single antibody does not represent the whole genus of antibodies that can bind to the claimed epitopes (VKHPVTGQF, IERIPEL and LNENSYVPREAGSQKDEN). Therefore, the specification of the instant case does not provide adequate description to support the scope of these claims.
It is well established in the art that the formation of an intact antigen-binding site of a given antibody requires the association of the complete heavy and light chain variable regions, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway et al 2022, Chapter 4).
It is also well known that compatible pairing of heavy chain (He) and light chain (Le) that allows generation of a functional and stable antibody is achieved in vivo through random combinatorial gene rearrangement, followed by stringent selection processes in the bone marrow, where only B cells producing well-paired, stable H-L chains survive (Janeway et al, Chapter 8). In contrast, when developing therapeutic antibodies ex vivo, identifying cognate
pairing is a significant challenge. Therefore, it is known in the art that not every heavy-light
combination forms a stable or functional antibody and to distinguish cognate from random H-L pairs is not an easy task.
Regarding antibody sequence variabilities implicated in claims 1 and 17, it is known in the art that even single amino acid changes in a CDR can abrogate the antigen binding function of an antibody (Rudikoff et al, see entire document, particularly the abstract and the middle of the left column of page 1982). More recently, Rabia et al (2018) "Understanding and overcoming trade-offs between antibody affinity, specificity, stability, and solubility" Biochem Eng. J. 15(137); 365-374 discusses the challenges with optimizing antibody properties and states that "natural antibody affinity maturation relies on the introduction of somatic mutations followed by clonal selection of antibody variants with improved affinity. However, not all somatic mutations contribute to antibody affinity ... antibodies accumulate some somatic mutations to increase affinity and others to compensate for the destabilizing effects of affinity-enhancing mutations" (page 2, paragraph 4). Rabia further provides an example of researchers who introduced mutations throughout variable frameworks and CDRs and created libraries to sort antibody variants with high antigen binding. In this case an antibody was identified that displayed increased affinity but had a significant reduction in stability (page 3, paragraph 2). Rabia concludes by stating that "a final key area of future work is the development of improved computational methods for predicting mutations in antibody CDRs and frameworks that cooptimize multiple antibody properties" and that "future efforts will also need to improve structural predictions of antibody CD Rs - especially the long and highly variable heavy chain CDR3 - to accurately predict CDR mutations that are beneficial to different antibody properties" (page 9, paragraph 4 - page 10 paragraph 2).
Based on the teachings of Rabia, introducing mutations or alterations in the antibody
structure, particularly in the CDR regions, is not a predictable task and requires
experimentation following mutation to ensure that the binding affinity is maintained and a
specific, stable antibody is created. These teachings demonstrate that a modification to even
one amino acid of an antibody, particularly in the CDRs, would likely result in an antibody that is
not suitable for binding as recited in the instant claims.
Regarding possible antibody variants with conservative substitutions of amino acid residues in antibody sequence recited in the specification of the instant case, Lees et al. "Investigating substitutions in antibody-antigen complexes using molecular dynamics: a case study with broad-spectrum, influenza A antibodies." Frontiers in Immunology 8 (2017): 143 discusses a study on the impact of single amino acid substitutions on antibody-antigen binding energy using three broad-spectrum antibodies to influenza A hemagglutinin and find that in some cases the impact of a substitution is local, while in others it causes a reorientation of the antibody with wide-ranging impact on residue-residue interactions: this explains, in part, why the change in chemical properties of a residue can be, on its own, a poor predictor of overall
change in binding energy (page 1, Abstract). Through AA substitutions in HA epitope and paratope in the three antibodies, Lees et al recites, "predictions made on the basis of chemical properties or straightforward inferences of critical residues may not be reliable."
Therefore, based on the importance of the CDR sequences in the variable region of an antibody taught by Rudikoff et al and Rabia et al, and the teaching of Lees et al which suggests that chemical similarity between residues should not be taken to imply sequence or structural invariance, which is critical to antibody function, the instant application fails to provide sufficient description regarding antibody sequence variations in claims 1 and 17 such that a person with ordinary skills in the art would be able to discern a structure/function correlation for the antibodies with the claimed variations.
Regarding claim 17 that recites antibody or antigen binding fragment that bind to specific epitopes on hTfR, which are functional limitations that encompass genera of antibodies by what they do (function), rather than by what they are (structure), MPEP 2173.05(g) teaches that "Unlimited functional claim limitations that extend to all means or methods of resolving a problem may not be adequately supported by the written description or may not be commensurate in scope with the enabling disclosure, both of which are required by 35 U.S.C. 112(a) and pre-AIA 35 U.S.C. 112, first paragraph. In re Hyatt, 708 F.2d 712, 714, 218 USPQ 195, 197 (Fed. Cir. 1983); Ariad, 598 F.3d at 1340, 94 USPQ2d at 1167. For instance, a single means claim covering every conceivable means for achieving the stated result was held to be invalid under 35 U.S.C. 112, first paragraph because the court recognized that the specification, which disclosed only those means known to the inventor, was not commensurate in scope with the claim. Hyatt, 708 F.2d at 714-715, 218 USPQ at 197."
In claim 17, the recited antibodies are based on the epitope to which they bind, not
the structure of the antibodies that would result in the claimed functions. The prior art also does not provide a representative number of species of antibodies having the claimed function nor does the prior art provide a structure-function correlation that could be used to identify such antibodies. Rather, the teaching of the prior art demonstrate that epitope binding is not predictable.
For instance, Hummer et al (2022) "Advances in computational structure-based
antibody design" Current Opinion in Structural Biology 74(102379); 1-7 teaches that the
traditional methods for antibody development, such as deriving antibodies from hybridomas of
inoculated animals or from library assembly followed by display techniques are not only costly
and time consuming but also are not necessarily able to produce antibodies that bind to the
desired site (epitope) on an antigen. Hummer teaches that computational antibody design
methods offer a way to overcome these limitations, but are held back by the lack of accurate
antibody and antigen structures (page 1, right column, paragraph 2). Hummer provides a
review on how advances in protein structure prediction and other areas are bringing us closer
to being able to entirely computationally designed antibodies that bind strongly to a defined
epitope (page 1, right column, paragraph 3), demonstrating that in 2022 predictable structure
function relationships were still not known. Hummer acknowledges this in their discussion of
future directions stating that "Several challenges still remain for true computational structure based antibody design. While there has been great progress in protein structure prediction,
current methods are not yet able to accurately predict the position of the side chain atoms or
structural changes on binding. For antibodies, accurately modeling the CDR-H3 loop remains a
major obstacle. Additionally, improvements in paratope and epitope prediction, both in terms
of accuracy and specificity (predicting the types of binding interactions for residues), will be
needed to help improve docking for high-throughput virtual screening." (page 4, column 2,
paragraph 3).
Hummer's teaching regarding the difficulties in predicting the relationship between
antibody structure and the epitopes to which they bind demonstrates a lack of predictability in
the field between antibody structure and function.
Taken together, it is not evident from the disclosure, that applicant was in possession of a representative number of species supporting the entire genera of antibodies that are encompassed by claims 1 and 17. Additionally, there is no disclosed or art recognized structure-function relationship between antibody structure and functionality which would allow for the predictable substitution of amino acids in the claimed sequences while maintaining binding function. Therefore, claims 1 and 17 were found not to meet the written description requirement.
Claims 20, 44, 45, 48, 49, 52, 53, 55, 57, 58, 59, 61, 64, 83, 95, 96, 97, 100, 102, 103, 106, 108, 109, 112, 114, 115, 118, 120, 121, 124, 126, 127, 128, 129, 132, 134, 136, 137, 140, 141, 143, 144, 145, 148, 149, 151, 155, 158, and 160 are directly or indirectly dependent on claims 1 and 17 and do not fix the issue of these claims, therefore these claims inherent the issue of claims 1 and 17 and do not meet the written description requirement.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 21, 25, 43, 76, 98, 99, 101, 110, 111, 113, 116, 117, 119, 122, 123, 125, 138, 139, 142, 146, 147, 150, 152, 153, 154, 156, 157, 159 are rejected under 35 U.S.C. 102 as being anticipated by Sonoda et al, “Anti-human transferrin receptor antibody capable of penetrating blood brain barrier” (US patent US10759864, September 1, 2020).
Claim 21 recites a fusion protein comprising an antigen-binding protein that binds specifically to transferrin receptor or an antigenic-fragment thereof or variant thereof fused to a payload, wherein the antigen-binding protein binds to human transferrin receptor with a KD of about 41nM or a stronger affinity.
Claim 25 recites a fusion protein comprising an antigen-binding protein that binds specifically to human transferrin receptor, which comprises a heavy chain variable region (HCVR or VH) and a light chain variable region (LCVR or VL), which is fused to an alpha-glucosidase polypeptide (GAA), wherein a Fab having said VH and VL binds to human transferrin receptor with a KD of about 0.65 nM or a greater affinity; and wherein, when said fusion protein is administered to a mouse expressing human transferrin receptor in the brain, the mouse achieves a molar ratio of mature GAA protein in the brain:serum GAA protein, in the mouse, of about 1:1 or greater when normalized against said ratio in mouse expressing mouse transferrin receptor that was administered 8D3.
Claim 43 recites a fusion protein or antigen-binding protein that binds specifically to human transferrin receptor which has one or more characteristics, including 1) affinity (KD) for binding to human TfR at 25°C in surface plasmon resonance format of about 41 nM or a higher affinity; 2) affinity (KD) for binding to monkey TfR at 25°C in surface plasmon resonance format of about 0 nM (no detectable binding) or a higher affinity; and 3) when in anti-hTfR scFv:hGAA format, reduces glycogen stored in cerebrum, cerebellum, spinal cord, heart and/or quadricep when administered to mice expressing human transferrin receptor (optionally, lacking functional endogenous GAA).
Claim 76 recites a method for delivering a payload to a tissue or cell type in the body of a subject comprising administering, to the subject, an antigen-binding protein that binds specifically to transferrin receptor or an antigenic-fragment thereof or variant thereof to the subject fused to the payload.
Sonoda et al (2020) teach a fusion protein between anti-human transferrin receptor antibody, 3N, and human acidic a-glucosidase (hGAA), hGAA-anti-TfR (3N) (page 79, example 25) and a fusion protein between Fab anti-hTfR (3N), and hGAA, Fab GS-GAA (page 84, example 31). The antibody 3N bears a VH/VL pair with SEQ ID No. 65/48 (page 91). hGAA-anti-TfR and Fab GS-GAA exhibited a KD of <1x10-12 M and 4.04x10-10 M to human transferrin receptor, respectively, and a KD of <1x10-12 M and 1.52x10-8 M to monkey transferrin receptor, respectively (page 79, Example 27, Table 17-2).
Sonoda et al further teach that in a GAA-KO/hTfR-KI mouse model which lacks endogenous GAA and express human transferrin receptor, the group of mice administered with Fab GS-GAA at a dosage of 5 .0 mg/kg showed a remarkable decrease in concentration of glycogen in the right brain and the heart as compared to the group of mice administered with free hGAA at a dosage of 20 mg/kg (page 84, Example 32, Fig. 12). Glycogen level was reduced in diaphragm, quadriceps femoris muscle, soleus muscle and tibialis anterior muscle, indicating efficient delivery of the GAA enzyme into these tissues which reduced the glycogen level. Although Sonoda et al did not directly measure the level of GAA in the brain and serum in the mouse, the measurement of glycogen level demonstrated effective delivery of the GAA enzyme. These results indicate that Fab GS-GAA can be used as a therapeutic agent for Pompe disease, particularly as a therapeutic agent for Pompe disease accompanied by brain and/or heart dysfunction.
Therefore, the hGAA-anti-TfR (3N) taught by Sonoda et al anticipate the fusion protein comprising anti-hTfR fused to a payload with a KD of 41nM in claim 21. And the FAB-GS-GAA taught by Sonoda et al, that binds to human transferrin receptor at an affinity of ~0.4nM and can significantly reduce the glycogen level in the brain of a diseased mouse anticipates the fusion protein in claims 25 and 43 with stated functions and properties. And the method of using FAB-GS-GAA, an anti-TfR Ab fused to GAA (a payload) to deliver GAA to brain, heart and muscle anticipates the method in claim 76.
Regarding the pharmaceutical composition comprising, the isolated polynucleotide encoding, the host cell comprising, the method of making, the vessel or injection device comprising the fusion protein or antigen binding protein in claims 21, 25 or 43 that are recited in claims 98, 99 and 101, claims 116, 117 and 119, claims 122, 123, and 125, claims 130, 131 and 133, claims 138, 139, and 142, respectively, Sonoda et al depict a method of generating a pharmaceutical composition and a method of making the fusion protein, hGAA-anti-TfR antibody 3N, from polynucleotide constructs to transfection of host cells, culture of host cells and purification of expressed fusion protein in examples 11 (page 71) 22 (page 78), 25 and 26 (page 79). Briefly, a DNA fragment was artificially synthesized that encodes a protein in which the heavy chain (IgG4) of the humanized anti-hTfR antibody 3N was linked via a linkersequence (Glyu Ser) to hGAA. CHO cells (CHO-Kl) were transformed with pE-neo(HCGAA-3N(IgG4)) and pE-hygr(LC3) constructed in Example 11 to obtain a cell line expressing a fusion protein between hGAA and a humanized anti-hTfR antibody. This cell line was designated as hGAA-anti-hTfR antibody expressing cell line 3N(IgG4) (Example 25, page 79). GAA-anti-hTfR antibody 3N(IgG4) was produced following the method described in Example 22 using the hGAA-anti-hTfR antibody expressing cell line 3N(IgG4). Purified product (hGAA-anti-TfR antibody 3N) was formulated in PBS buffer and was used as a pharmaceutical agent to assess the in vivo pharmacological effect in monkey (example 28, page 79-81) and mouse (Example 29-31, page 81-84). Sonoda et al recites that the pharmaceutical agent can be prepared in a form suitable for parenteral administration for the treatment of a disease condition (page 66, column 101) and a type of aqueous preparations of the pharmaceutical agent can be a prefilled syringe (page 66, column 101 3rd paragraph).
Regarding the method of administering, the method of treating a lysosomal storage disease (LSD), and the method of treating a glycogen storage disease (GSD) in a subject in need thereof comprising administering to the subject an effective amount of the fusion protein or antigen binding protein in claims 21, 25 or 43 that are recited in claims 146, 147, and 150, claims 152, 152 and 154, claims 156, 157, and 159, respectively, Sonoda et al further teach that in an animal model of Pompe disease in which the GAA gene is disrupted and having a chimera TfR gene in heterology (GAA-KO/hTfR-KI mice, page 81, Example 29), intravenous administration of Fab GS-GAA at a dosage of 5 .0 mg/kg effectively reduced the concentration of glycogen in the right brain and the heart compared to free hGAA at a dosage of 20 mg/kg (page 84, Example 32, Fig. 12), as discussed above, indicating efficient delivery of the GAA enzyme into these tissues, and that the anti-TfR fusion protein, Fab GS-GAA, can be used as a therapeutic agent for Pompe disease, particularly as a therapeutic agent for Pompe disease accompanied by brain and/or heart dysfunction. Since Pompe disease is caused by defective lysosomal enzyme alpha-glucosidase (GAA), which results in the deficient processing of lysosomal glycogen, it is considered both a lysosomal storage disease (LSD) and glycogen storage disease (GSD).
Therefore, the teachings of Sonoda et al anticipates the limitations in claims 146, 147, 150, 152, 152, 154, 156, 157, and 159.
Claims 110, 111 and 113 recite a complex comprising the fusion protein or antigen-binding protein in claims 21, 25 and 43, respectively, bound to a human transferrin receptor polypeptide or antigenic fragment thereof. Sonoda et al recites in claim 9, a complex of the anti-hTfR antibody with the extracellular region of hTfR, of which the dissociation constant is not greater than 1x10-10 M, which meets the limitation in claim 113.
Sonoda et al further recite in Example 27, a method of measurement of the affinity of hGAA-anti-TfR antibody 3N (IgG4) and Fab GS-GAA with human TfR, where Octet RED96 was used to analyze the interaction between an antigen binding protein and an antigen, wherein the antigen used in the measurement is a recombinant human TfR, which had the amino acid sequence of the hTfR extracellular region with a histidine tag attached to the N-terminus. Table 17-2 shows the dissociation constant of a complex of hGAA-anti-TfR antibody 3N (IgG4) and Fab GS-GAA with the extracellular region of hTfR are < 1x10-12 M and 4.04x10-10 M, respectively, which meets the limitations in claims 110 and 111.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 104, 105 and 107 are rejected under 35 U.S.C. 103 as being unpatentable over Sonoda et al (US10759864, 2020), in view of Xu et al. "Improved efficacy of a next-generation ERT in murine Pompe disease." JCI insight 4.5 (2019): e125358, as evidenced by Do et al. "Challenges in treating Pompe disease: an industry perspective." Annals of translational medicine 7.13 (2019): 291.
Claims 104, 105 and 107 recite a composition or kit comprising the fusion protein or antigen-binding protein in claims 21, 25 and 43, respectively, or a pharmaceutical composition thereof in association with a further therapeutic agent.
Sonoda et al demonstrated that anti-TfR Fab-GAA fusion protein, Fab GS-GAA, can be used as a therapeutic agent for Pompe disease in a mouse model due to its efficient delivery of GAA into the brain, heart and other tissues. However, the teaching of Sonoda et al does not address other challenges in treating Pompe disease as discussed below.
Do et al (2019) recites that alglucosidase alfa enzyme replacement therapy (ERT) using recombinant human GAA (rhGAA ERT) for Pompe disease has provided irrefutable clinical benefits, but has not been an optimal treatment primarily due to inefficient targeting of active GAA to skeletal muscles and several factors contribute to this inefficiency (Abstract) including instability of rhGAA and immune response to rhGAA. rhGAA is an acid hydrolase that is most stable and active at acidic pH, but is substantially less stable at the neutral pH environment of blood that ultimately leads to irreversible enzyme inactivation (page 3, column 1, paragraph 2). Immune response to rhGAA in Pompe patients leads to development of anti-rhGAA antibodies that can reduce the activity of rhGAA by block the enzyme activity of rhGAA or enhancing its clearance (page 4, column 2, paragraph 2).
Xu et al developed a next generation enzyme replace therapy for Pompe disease by co-administering ATB200 (Amicus proprietary rhGAA) with a small-molecule pharmacological chaperone (PC), AT2221 (miglustat, N-butyl-deoxynojirimycin [NB-DNJ]. The combination therapy (ATB200/AT2221) is based on the principle that selective binding of the PC stabilizes the conformation of the enzyme GAA, thus improving its pharmacological properties. Xu et al teach that AT2221 binding enhanced the stability of ATB200 in vitro (Figure 1 A-D) and in vivo (Figure 1E, Table 1). In the study described in Table 1, ATB200 was administered i.v. with or without oral coadministration of AT2221, plasma GAA activity and its halflife increased significantly in NHPs co-treated with both ATB200 and AT2221 than ATB200 alone, indicating the stabilization effect of AT2221 on GAA activity (page 4, Table 1). Enhanced rhGAA activity in blood in the presence of the PC was also observed in ERT-treated patients with Pompe disease. In addition, improved tolerability and alleviation of infusion-associated reactions were reported following coadministration of miglustat and rhGAA. Overall, ATB200/AT2221 was substantially more potent than alglucosidase alfa in a mouse model of Pompe disease (Abstract, page 5-6, Figure 2, Table 2). These data highlight the potential advantages of coadministration of a PC on the pharmacokinetics (PK), safety, and tolerability of the replacement enzyme, ATB200 (rhGAA) (page 2, paragraph 2-3).
Since AT2221 can stabilize the GAA activity at neutral PH in the blood, an ordinary artisan would expect co-administration of AT2221 with i.v. injection of Fab anti-Tfr-GAA (Fab GS-GAA) taught by Sonoda et al would stabilize the enzyme activity of GAA, which would then allow higher enzymatic activity of GAA once it is delivered into the tissue by anti-TfR Fab, therefore enhancing its therapeutic effect.
Therefore, an ordinary artisan would be motivated to use a composition or kit comprising the Fab-GS-GAA and the pharmacological chaperone AT2221 to treat patients with Pompe disease by co-administering these therapeutic agents as taught by Xu et al (2019), and expect stronger therapeutic effects than Fab0DS-GAA alone, which meets the limitations in claims 104, 105 and 107.
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.
US application 19/099, 243
Instant claims 1, 17 and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 106-109 of copending Application No. 19/099,243, Zhang et al. “COMPOSITIONS AND METHODS FOR TRANSFERRIN RECEPTOR (TFR)-MEDIATED DELIVERY TO THE BRAIN AND MUSCLE” (filed 01/28/2025, herein App’243). Although the claims at issue are not identical, they are not patentably distinct from each other.
Claims 106-109 of Zhang et al (2025) recites 5 anti-TfR antibodies that bears identical HCVR/LCVRs with identical SEQ ID NOs and contain identical HCDRs/LCDRs pairs, as the instant case, as confirmed by sequence alignment. Based on the sequence alignment, antibody ID in TABLE A, page 62, epitope mapping results in Table 8-3 (Example 8), and the affinity to human TfR data in Table 2-2 of the instant disclosure, the 5 corresponding anti-TrR antibodies in App’243 would bind to the same epitopes, which match the epitopes recited in instant claim 17, and have the same affinity to human TfR, which are higher affinity than 41 nM, as the listed 5 antibodies in the instant case, as shown in the Table (1) below.
Table (1): TfR antibodies in App’243 anticipates TfR antibodies in instant case
HCVR/LCVR Seq ID (App’243, claim 109)
Anti-TfR antibody ID (Instant case)
HCVR/LCVR Seq ID N. (Instant case, claim 1 TABLE A)
Epitope seq (Instant case, claim 17, Table 8-3)
KD (M) to human TfR
Seq ID No. 262/267
H1H12845B
Seq ID No. 262/267
LLNE
1.18E-09
Seq ID No. 222/227
H1H12847B
Seq ID No. 222/227
TYKEL
1.62E-09
Seq ID No. 282/287
H1H12841B
Seq ID No. 282/287
LLNE
6.70E-10
Seq ID No. 122/127
H1H12798B
Seq ID No. 122/127
LLNE, TYKEL
3.87E-10
Seq ID No. 242/247
H1H12843B
Seq ID No. 242/247
LLNE, TYKEL
1.78E-09
Although claims 106-109 of App’243 recite a protein-drug conjugate comprising an antibody or antigen-binding fragment discussed above that is conjugated to a molecular cargo, which is not defined as a protein in App’243, the antibody or antigen-binding fragment portion of the protein-drug conjugate is identical to the antigen binding protein in instant claim 1 and they bind to corresponding epitopes that are recited in claim 17, and have higher affinity than 41nM, as discussed above. Therefore, claims 106-109 of App’243 anticipate instant claims 1, 17 and 43.
Instant claims 49, 114, 119; 52, 120, 125; 53, 126, 127; 55, 57, 128, 133 recites an isolated polynucleotide encoding the antigen-binding protein of claim 1, a vector containing the polynucleotide of claim 1, a host cell comprising the antigen-binding protein of claim 1, and a method of making the antigen-binding protein, and a product of the method, respectively. Since the antigen-binding protein of claim 1 is anticipated by App’243 as discussed above, it is well within an ordinary artisan’s capability to generate the polynucleotide encoding the antigen-binding protein of claim 1, the vector that contains it, a host cell comprising the antigen-binding protein of claim 1 using the conventional recombinant DNA technology which is well established in the art, and obtain an antigen binding protein which is a product of the method. Therefore, instant claims 49, 114, 119; 52, 120, 125; 53, 126, 127; 55, 56, 57, 128, 133 are anticipated by App’243.
Instant claims 44 and 96, 101; 45, 102 and 107, 48, 108 and 113 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 131, 132 and 134 of App’243, respectively. Although the claims at issue are not identical, they are not patentably distinct from each other.
Claim 131 of App’243 recites a pharmaceutical composition comprising the protein-drug conjugate of claim 106 and a pharmaceutical carrier.
As discussed above, the protein portion of the protein-drug conjugate in claim 106 of App’243 is identical to the antigen binding protein of instant claims 1, 17 and 43. The pharmaceutical composition of the protein-drug conjugate in claim 131 of App’243 would anticipate a pharmaceutical composition that is compatible with the protein portion in these claims, which meets the limitations of instant claims 44, 96 and 101. As such, claim 132 of App’243 which recites the pharmaceutical composition in claim 131, in association with a further therapeutic agent, meets the limitation of instant claim 45, 102 and 107. Similarly, claim 134 of App’243 which recites a complex comprising the protein-drug conjugate of claim 106, bound to a human transferrin receptor polypeptide or a fragment thereof, meets the limitation of instant claims 48, 108 and 113.
Instant claims 58, 135, 136, 142; and 59, 143, 144 and 150 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 135, 136, and 137 of App’243. Although the claims at issue are not identical, they are not patentably distinct from each other.
Instant claims 58, 135, 136, 142; and 59, 143, 144 and 150 recite a vessel or injection device comprising the antigen-binding protein of claims 1, 17 or 43 a method for administering the antigen-binding protein of claim 1, 17 or 43 to a subject comprising introducing the protein into the body of the subject, respectively. Claims 135, 136, and 137 of App’243 recite methods comprising administering to a subject an effective amount of the protein-drug conjugate with the protein portion identical to the antigen binding protein of instant claim 1, including parenteral administration of the protein drug conjugate, these claims anticipate a method of administering to a subject the antigen-binding protein in instant claims 1, 17 or 43 and a suitable injection device, therefore, meeting the limitations of instant claims 58, 135, 136, 142; and 59, 143, 144 and 150.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Instant claims 20, 21, 25, 95, 134, 61, 64, 76, 83, 115-118, 121-124, 129-132, 137-141, 145-149, 151-155 and 156-160 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 106-109 of App’243 in view of Sonoda et al (2020).
Claims 106-109 of App’243 teach anti-TfR antibody or antigen binding fragment thereof that binds to human TfR conjugated to a molecular cargo, wherein the antibody or antigen binding fragment anticipate the antigen binding protein in claims 1, 17, 20, and 25, as discussed above. Since the affinity of these antibody to human TfR is higher than 41 nM as shown in Table (1), these antibodies anticipate antibody in instant claim 21.
However, App’243 does not reach an anti-TfR antibody fused to a protein payload.
Sonoda et al (2020) teach an anti-TfR Fab fused to GAA, Fab GS-GAA, that can effectively reduce glycogen level in the brain, heart and muscle tissue in a GAA-KO/hTfR-KI mouse model for Pompe disease, suggesting its utility as a therapeutic agent for Pompe disease, as discussed above.
It would have been obvious for a person with ordinary skill in the art to utilize the anti-TfR antibody in claims 106-109 of App’243, which anticipates antibodies in instant claims 1, 17, 20, 21 and 25 and fuse them with GAA as taught by Sonoda et al (2020), and expect the resultant fusion protein to be able to effectively deliver the GAA enzyme into the brain, heart and muscle tissue in a mouse model of Pompe disease and reduce the glycogen levels, therefore can be used to treat Pompe disease, which meets the limitations in claims 20, 21, 25, 95, 134, 61, 64 and 76.
Regarding instant claims 83, 129-132 that recite methods of expressing or making the fusion protein comprising the anti-TfR antibody and instant claims 115-118, 121-124 that recites the polynucleotide encoding and host cells comprising the fusion protein in instant claims 1, 17, 20, 21, 25, Sonoda et al (2020) teach methods, polynucleotides, host cells, pharmaceutical compositions, that would allow an ordinary artisan to use the antibodies recited by App’243 to generate a GAA fusion protein, which meets the limitation of these claims.
Regarding instant claims 137-141, 145-149, 151-155, 156-160 that recite a vessel or injection device comprising, a method of administering, a method of treating or preventing a lysosomal storage disease comprising administering to the subject an effective amount of, and a method of treating or preventing a glycogen storage disease comprising administering to the subject an effective amount of the fusion protein in claims 20, 21, 25, 43, 95 or 134, respectively, Sonoda et al taught a prefilled syringe, the method of administering Fab GS-GAA at a dosage of 5 .0 mg/kg effectively reduced the concentration of glycogen in the right brain and the heart in GAA-KO/hTfR-KI mouse model of Pompe disease, which is a LSD and GSD, suggesting effective methods of treating these diseases, as discussed above.
Therefore, a person with ordinary skill in the art would be motivated to utilize the anti-TfR antibody recited in App’243 to generate anti-TfR-GAA fusion proteins, as taught by Sonoda et al, and administer an effective amount of the fusion protein to a subject with LSD or GSD and expect effective delivering of GAA into the diseased tissue and reduce glycogen level.
Instant claims 97-101, 103-106, 109-112 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 106-109, 131, 132 and 134 of App’243 in view of Sonoda et al (2020).
Claims 131, 132 and 134 recite a pharmaceutical composition comprising the protein-drug conjugate of claim 106 and a pharmaceutically acceptable carrier, the pharmaceutical composition of claim 131, in association with a further therapeutic agent and a complex comprising the protein-drug conjugate of claim 106, bound to a human transferrin receptor polypeptide or a fragment thereof, respectively. An ordinary artisan would be able to utilize these teachings with the fusion proteins comprising anti-TfR-GAA generated using the methods described above and arrive at the pharmaceutical compositions in instant claims 97-101, the compositions with a further therapeutic agent in instant claims 103-106 and the complexes in instant claims 109-112.
This is a provisional nonstatutory double patenting rejection.
Conclusion
All claims are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HONG REN whose telephone number is (571) 272-3913. The examiner can normally be reached Monday-Friday, 9-5.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://W\NW.uspto.gov/interviewpractk:e..
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Joanne Hama can be reached at (571) 272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit:
https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/HONG REN/
Examiner, Art Unit 1647
/JOANNE HAMA/
Supervisory Patent Examiner, Art Unit 1647
Prosecution Insights