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 .
Election/Restrictions
The Examiner called John C. Gratz on 08/25/2025 for a provisional election of species of anti-PD-L1 antibody which is i) 5G11 comprising the heavy chain CDR1-3 (HCDR1-3) of SEQ ID NO:1-3, respectively, and light chain CDR1-3 (LCDR1-3) of SEQ ID NO:7-9, respectively, or ii) 13C5 comprising the HCDR1-3 of SEQ ID NO:4-6, respectively, and LCDR1-3 of SEQ ID NO:10-12, respectively. However, in view of the joint disclosure of both antibody species in the same prior art (e.g., WO 2016/022630, cited in the IDS filed 11/07/2024), the requirement for election of species has been reconsidered and is withdrawn. Both species are examined.
Claim Interpretation
There is no definition of “% homology” in the specification. It is being assumed to be interchangeable with “% identity”. This is different than using the term “homology” alone without a percentage associated therewith. This is consistent with Pearson et al. (Curr. Prot. Bioinformatics, 42.1, 2013, 9 pages, cited in the IDS filed 11/07/2024).
Specification
All references to location in the specification are to the paragraph numbering used in the pregrant publication of this application, US 2023/0285545.
Title
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
The following title is suggested:
ANTI-PD-L1 ANTIBODY AND ANLOTINIB COMBINED
Claim Rejections - 35 USC § 112(b)
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 35 is 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 35 requires the anti-PD-L1 antibody comprise a heavy chain variable region and light chain variable region of one of 4 humanized antibodies described only by laboratory designated name in the claims (hul3C5-hIgGl, hul3C5-hIgG4, hu5G11-hIgGI and hu5G11-hIgG4). The names are merely laboratory designations which do not clearly define the products of the claims, since different laboratories may use the same laboratory designations to define completely distinct antibodies (see, e.g., US 2004/0120947 teaches DR4 antibody 5G11). While it is disclosed that these antibodies are taught in the prior art ([0067]) and the CDR sequences are disclosed, the specification presents a broad definition, e.g., “In one embodiment, hu5G11-hIgG1 has a heavy chain amino acid sequence set forth in SEQ ID NO: 17, and a light chain amino acid sequence set forth in SEQ ID NO: 18.” Note this is merely “one embodiment” and not a limiting definition sufficient to define the VH or VL of any of the named antibodies. Further, while paragraph [0068] sets forth the examples of VH and VL domains identified by SEQ ID NO:, the sequences are not linked to a named antibody. There is no single definition of the VH or VL of any of hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1, and hu5G11-hIgG4 to provide sufficient clarity. The antibodies are not deposited (see MPEP 2404). Because the specification lists the VH, VL, HC and LC of the antibodies by SEQ ID NO: (with the exception of hu13C5-hIgG HC), reference in the claims to SEQ ID NO: instead of name could obviate this rejection.
Claim Rejections - 35 USC § 112(a)
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 14-23, 32 and 34-41 are 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 a method of treating soft tissue sarcoma (STS), comprising administering a therapeutically effective amount of anlotinib or a pharmaceutically acceptable salt thereof, and an anti-PD-L1 antibody comprising the heavy chain CDR1-3 (HCDR1-3) of SEQ ID NO:1-3 and light chain CDR1-3 (LCDR1-3) of SEQ ID NO:7-9 or HCDR1-3 of SEQ ID NO:4-6 and LCDR1-3 of SEQ ID NO:10-12, does not reasonably provide enablement for wherein the anti-PD-L1 antibody CDRs, variable regions or heavy and light chains are mixed-and-matched among or between antibodies hu13C5 and hu5G11 or wherein the CDRs within a variable region are not identical to the above. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Independent claim 14 is drawn to a method of treating soft tissue sarcoma, comprising administering a therapeutically effective amount of anlotinib or a pharmaceutically acceptable salt thereof, and an anti-PD-L1 antibody comprising HCDR1 region having at least 80% homology to an amino acid sequence set forth in SEQ ID NO: 1 or SEQ ID NO: 4; or a HCDR2 region having at least 80% homology to an amino acid sequence set forth in SEQ ID NO: 2 or SEQ ID NO: 5; or a HCDR3 region having at least 80% homology to an amino acid sequence set forth in SEQ ID NO: 3 or SEQ ID NO: 6; or a LCDR1 region having at least 80% homology to an amino acid sequence set forth in SEQ ID NO: 7 or SEQ ID NO: 10; or a LCDR2 region having at least 80% homology to an amino acid sequence set forth in SEQ ID NO: 8 or SEQ ID NO: 11; or a LCDR3 region having at least 80% homology to an amino acid sequence set forth in SEQ ID NO: 9 or SEQ ID NO: 12. For the claimed method to be enabled, the anti-PD-L1 antibody must be able to help treat STS. Therefore, it must have sufficient affinity and have other pharmacokinetic properties that allow it to bind PD-L1 and block its association with its receptor, PD-1, with sufficient specificity to at least inhibit growth of the sarcoma in order for the antibody to be used in the claimed method of treatment. Treatment as defined in the specification ([0175]) encompasses “any treatment to a disease in a patient, including (a) inhibiting a symptom of a disease, i.e., blocking the progression of the disease; or (b) alleviating a symptom of a disease, i.e., causing remission of the disease or the symptom.” As a result, the antibody needs to possess at least one of those abilities, and to do so it must bind with sufficient affinity and have other conducive pharmacokinetic properties to be used with a reasonable expectation of success.
The specification discloses only 2 species of anti-PD-L1 antibody within the instant claim scope, which encompasses amino acid variants (deletion/ addition/ substitution) of antibodies 5G11 and 13C5 of which no variants are exemplified. These have the respective heavy chain CDR1 (HCDR1) of SEQ ID NO:1-3 and light chain CDR1-3 (LCDR1-3) of SEQ ID NO:7-9 (5G11) or HCDR1-3 of SEQ ID NO:4-6 and LCDR1-3 of SEQ ID NO:10-12 (13C5). They have the respective variable heavy and light chain regions (VH and VL) of SEQ ID NO:13 and 15 (5G11) and SEQ ID NO: 14 and 16 (13C5). These are encompassed by the heavy chain (HC) and light chain (LC) of SEQ ID NO:17 and SEQ ID NO:18 or 21 (5G11) or SEQ ID NO:17 and 19 (13C5).
For an antibody or antigen-binding fragment thereof, it is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework (FR) sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen-binding sites. 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 Chen et al. (EMBO J. 14 (12): 2784-2794, 1995), which teaches that the substitution of a single amino acid in CDR-H2 (HCDR2) of an antibody can totally ablate antigen binding and that the same substitution in closely related antibodies can have opposite effects on binding (e.g., see entire document, including Figure I). The authors compared the effects of identical substitutions in related anti-phosphocholine antibodies DI6 and TI5, and as shown in Figure 3 some substitutions increased antigen binding in one antibody while ablating it in the other. While other amino acid changes in antibodies produced only small or insignificant changes in binding affinity, the complexity of antigen binding and affinity by antibodies is high. Lamminmaki et al. (J. Biol. Chem. 276:36687, 2001) showed with the crystallographic structure of an anti-estradiol antibody complex that although HCDR3 played a predominant role in antibody binding, all CDRs in the light chain made direct contact with the antigen (p. 36693, col. 2, first two paragraphs). MacCallum et al. (J. Mol. Biol 262:732, 1996) analyzed a variety of antibodies for their interaction with their antigen and found that although CDR-H3 dominated the interaction, a number of residues outside the CDRs make antigen contact and residues in the CDR which do not contact antigen are important for backbone conformations (e.g., p. 733, section beginning at the end of col. 1, and p. 735, paragraph bridging cols. 1-2). The CDR-H3 of SEQ ID NO:3 is only 8 amino acids. If one amino acid is changed in the HCDR3 (i.e., a sequence 88% identical thereto), that represents a 12% change and 160 possible CDR-H3 sequences (assuming substitution of any of the 20 natural amino acids). There is no reasonable expectation that an antibody comprising a substituted HCDR3 or other CDR(s) would bind PD-L1 with sufficient affinity to be used therapeutically, nor does the specification provide guidance or direction about which substitutions, additions or deletions throughout the variable region could be made with a reasonable expectation of successfully maintaining the necessary antibody specificity and function to be used. This is emphasized by the very specific and limited backmutations made in the framework regions of the humanized form of antibodies 5G11 and 13C5 (WO 2016/022630, [0109], cited in the IDS filed 11/07/2024). For activity in the claimed method, the antibody must not only bind PD-L1, it reasonably appears that it must inhibit its binding to its receptor, PD-1, so that the negative regulation signal does not function (see WO2020239085 at [0003], cited in the IDS filed 02/09//2023].
An additional enablement issue for limitations of claims 14, 32, 34 and 35 is the permissiveness of the mixing of CDRs from the two antibody or mixing of VH/VL or HC/LC. The prior art does not support the reasonable expectation of successfully making a functional antibody or antigen-binding fragment thereof under these circumstances. It has been shown that mixing the heavy chains of an antibody to p-azobenzoate from one rabbit with the light chains of an antibody to the same compound but from a different rabbit produced low activity antibodies. It is concluded (RS Nezlin, Biochemistry of Antibodies, 1970, p. 160), "Thus, to restore activity it is not sufficient that the two chains are combined. It is also necessary that the two chains possess a certain specificity if the antigen-binding capacity is to be restored." Later, Kranz et al. (Proc. Natl. Acad. Sci., USA, 78(9):5807 -5811, 1981) showed that in mixing heavy and light chains from six monoclonal anti-fluorescyl antibodies, heterologous heavy and light chain mixtures did not form anti-fluorescyl active sites (p. 5809, col. 1, first part of second paragraph). In another experiment (supra, p. 5809, col. 1, third paragraph), “Of the 30 possible heterologous H and L chain combinations, 13 did not reassociate within detectable limits…, 13 reassociated but with less affinity than the homologous association,.. and 4 associated with greater affinity than the homologous reassociation….” Herold et al. (Scientific Reports, 7:12276, 2017), showed by mutating conserved regions of VH and VL, almost all VH mutants led to decreased antigen-binding affinity, while the VL was more permissive (p. 4, 2nd and 3rd paragraphs). However, when CDR regions were switched between variable domains, it was found that for the VH binding to antigen not only the CDRs but framework regions were also a determining factor (p 9, 6th paragraph). Herold et al. concludes (p. 14, end of 2nd paragraph and 3rd paragraph), “[B]inding to the antigen is affected by each CDR loop differently and changes in loop mobility can in principle affect antigen binding affinity in an unpredictable way. (¶) Taken together our data indicate that multiple determinants regulate the VH/VL association and the affinity for the antigen. The interplay between interface interactions and CDRs turned out to be complex with mutual influences on VH/VL association and antigen binding.” The specification does not disclose that different pairings of CDRs or variable domains, such as the VH of SEQ ID NO:13 and VL of SEQ ID NO16, could pair to form a PD-L1-binding antibody with an affinity sufficient for use as required by the claims. This supports both the complexity of the structure-function relationship of antigen binding as well as the unpredictability of using a non-antibody scaffold for the CDRs to obtain a PD-L1-binding antibody.
Therefore, for the reasons discussed above and including the breadth of the claims as they relate to amino acid variants which may be in the CDR(s), the support by the prior art of the complexity and unpredictability of antigen binding as it relates to the CDR as well as variable regions, the paucity of working examples of any modified CDRs of particular anti-PD-L1 antibodies that can function within the context of the claimed therapeutic method, and the lack of guidance for or direction about which modifications and/or substitutions would reasonably be expected to produce a therapeutically functional antibody, it would require undue experimentation to make and use the claimed invention.
Claims 14-23 and 32-41 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.
Independent claim 14 is drawn to the treatment of soft tissue sarcoma (STS) by administering a therapeutically effective amount of an anti-PD-L1 antibody and anlotinib, wherein the anti-PD-L1 antibody comprises one of two of each of heavy and light CDR1-3 or a CDR 80% homologous (identical) thereto. These CDRs are from prior art humanized anti-PD-L1 antibodies hu5G11 and hu13C5 ([0067]). While claims 32 and 33 remove the limitation directed to homology, they still allow mixing-and-matching of CDRs from the two different antibodies. Claim 34 is similar, allowing for mixing-and-matching between variable heavy and light chain regions (VH and VL) of specific sequences (SEQ ID NO:13 and 15 of hu5G11 and SEQ ID NO:14 and 16 of hu135C) and sequences 80% homologous thereto. Claim 35 permits mixing of heavy and light chain variable regions. However, 13C5 and 5G11 are two distinct antibodies. There is no disclosure of CDRs that are different from those disclosed for either antibody 5G11 or 13C5 in an antibody meeting the broad limitations of the claims and that could bind PD-L1 and be used in the claimed method. Further, there is no disclosure that part of one antibody, e.g., a heavy chain, could pair with a part of another distinct antibody, e.g., a light chain, to form an anti-PD-L1 antibody that in combination with anlotinib and additionally at the concentration or dosages set forth in the instant claims could be used to treat a STS. There are two related issues under the written description provision of 35 USC 112(a) for the claims: 1) antibodies comprising CDRs or variable domains that are different from those disclosed, and 2) antibodies comprising CDRs and/or variable domains from two different antibodies, i.e.¸ mixing-and-matching parts of two different antibodies to make a single antibody.
An antibody that binds PD-L1 and comprises CDR-H1-3 of SEQ ID NO:1-3 and CDR-L1-3 of SEQ ID NO:7-9 or SEQ ID NO:4-6 and SEQ ID NO:10-12, and/or wherein the VH is SEQ ID NO:13 and VL is SEQ ID NO:15 or VH is SEQ ID NO:14 and VL is SEQ ID NO:16, respectively, or the heavy chain (HC) comprises SEQ ID NO:17 and light chain (LC) comprises SEQ ID NO:18 or 21 or the HC comprises SEQ ID NO:17 and LC comprises SEQ ID NO:19, meets the written description provision of 35 USC 112(a) for claims 14-17, 20, 23, 32-36, 39 and 41. Because claims 18, 19, 21, 22, 37, 38 and 40 require the antibody be usable in a particular dosage or dosage range and because as discussed below it is not only the CDRs but the context of the CDRs that determines antibody pharmacokinetics, only anti-PD-L1 antibodies comprising at least the VH/VL pair of 5G11 or 13C5 meets the written description for these more specific claims. However, the claims are directed to or encompass antibodies, which includes by definition in the specification antigen-binding fragments thereof ([0169]), having sequences that comprise a mixture of CDRs, VH, VL, HC or LC from the two different antibodies (5G11 and 13C5), or that comprise sequence variants or that have a recited degree of homology, none of which are disclosed. Prior art murine and humanized antibodies that have the same VH and VL CDR1-3 sequences are disclosed in WO 2016/022630 (cited in the IDS filed 11/07/2024). The importance of antibody sequence in antigen binding is emphasized by the very specific and limited backmutations made in the framework regions of the humanized form of antibodies 5G11 and 13C5 (WO 2016/022630 in paragraph [0109]). The particular humanized VH and VL of that WO document and the instant application are specifically disclosed but variants thereof are not. The skilled artisan could not readily envision these other encompassed antibodies or antigen-binding fragments thereof. None of these meets the written description provision of 35 USC 112(a).
The anti-PD-L1 antibody of the claims must be therapeutically effective in the treatment of STS in combined with administration of anlotinib or a pharmaceutically acceptable salt thereof. Therefore, the skilled artisan would reasonably expect that in order for the antibody to be therapeutically effective it must bind its antigen with sufficient affinity and specificity to be able to treat a STS. Treatment as defined in the specification ([0175]) encompasses “any treatment to a disease in a patient, including (a) inhibiting a symptom of a disease, i.e., blocking the progression of the disease; or (b) alleviating a symptom of a disease, i.e., causing remission of the disease or the symptom.” As a result, the antibodies of the claims need to possess the function of at least one (a) or (b) and to do so must bind with sufficient affinity and have other conducive pharmacokinetic properties to be used with a reasonable expectation of success.
For an antibody, it is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain the required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen-binding sites. 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 Chen et al. (EMBO J. 14 (12): 2784-2794, 1995), which teaches that the substitution of a single amino acid in CDR-H2 of an antibody can totally ablate antigen binding and that the same substitution in closely related antibodies can have opposite effects on binding (e.g., see entire document, including Figure 1). The authors compared the effects of identical substitutions in related anti-phosphocholine antibodies DI6 and TI5, and as shown in Figure 3, some substitutions increased antigen binding in one antibody while ablating it in the other. While other amino acid changes in antibodies produced only small or insignificant changes in binding affinity, the complexity of antigen binding and affinity by antibodies is high. Even though there are some publications which acknowledge that CDR-H3 is important, the conformations of other CDRs as well as FRs influence binding. There is no information in the specification about which amino acids of the CDRs and/or FRs are necessary and/or sufficient for specific PD-L1 binding other than those of antibodies 13C5 and 5G11 ([0067]). There is no descriptive support of amino acid substitutions in the CDRs or VH or VL encompassed by 80% identity. Amino acids both in and outside of CDRs are important for antigen binding and pharmacokinetic properties. This is in line with the teachings of Lamminmaki et al. (J. Biol. Chem. 276:36687, 2001) which showed with the crystallographic structure of an anti-estradiol antibody complex that although CDR-H3 played a predominant role in antibody binding, all CDRs in the light chain made direct contact with the antigen, with CDR-L2 also functioning to stabilize CDR-H3 (p. 36693, col. 2, first two paragraphs). MacCallum et al. (J. Mol. Biol 262:732, 1996) analyzed a variety of antibodies for their interaction with their antigen and found that although CDR-H3 of the variable heavy chain dominated the interaction, a number of residues outside the CDRs make antigen contact and residues in the CDR which do not contact antigen are important for backbone conformations (e.g., p. 733, section beginning at the end of col. 1, and p. 735, paragraph bridging cols. 1-2). For larger antigens, such as proteins like PD-L1, most of CDR-L2 and several residues of CDR-H1 and CDR-L3 typically make contact (p. 733, last paragraph). It is concluded (p. 742, col. 2, middle of second paragraph), “Antigens tend to bind to the antibody residues located at the centre of the combining site where the six CDRs meet….” The instant heavy chain CDR3 5G11 and 13C5, respectively SEQ ID NO:3 and 6, has only 8 amino acids. They are extremely different sequences. Also, even if just one amino acid is changed in a CDR-H3, that represents a 12% change and 160 possible CDR-H3 sequences (assuming substitution of any of the 20 natural amino acids). The number of possible antibody sequences increases dramatically considering additional permission of 80% identity to the other 5 CDRs. Even for the variable heavy and light chain regions, 80% identity means changes in 21-23 amino acids per region. The limited disclosure of specific functional embodiments encompassed by the claims and evidence in the prior art that the effect of amino acid substitutions in CDRs does not allow the skilled artisan to readily envision a representative number of antibody species to support the broad genus encompassed by the claims, nor does it appear the inventors were in possession of the broadly claimed genus.
The specification does not provide guidance or direction for the placement of the CDRs into other than the disclosed corresponding framework regions found in the respective variable domains for an antibody or fragment thereof with the required functional characteristics. The CDR1-3 make up only about 28% of each of the VH and VL. Additionally, the prior art shows that not only the CDRs of an antibody, but also FR are important for functional characteristics of antibodies. For example, Sela-Culang et al. (Front. Immunol. 4:302, 13 pages, Oct. 2013; p. 7, paragraph bridging cols. 1-2) states, “Framework region residues that affect Ag binding can be divided into two categories. The first are FR residues that contact the Ag, thus are part of the binding-site (108, 109, 111, 116-123). Some of these residues are close in sequence to the CDRs (in fact they may be within the boundaries of CDRs according to some CDR identification methods, but not according to others, as shown in Figure 3). Other residues are those that are far from the CDRs in sequence, but are in close proximity to it in the 3-D structure.” Binding affinity and ligand-blocking activity depend on the 3-D structure of the antibody and how it interacts with other proteins. This is also examined by Herold et al. (Scientific Reports, 7:12276, DOI:10.1038/s41598-017-12519-9, Sept. 2017), showing by mutating conserved regions of VH and VL that almost all VH mutants led to decreased antigen binding affinity, while the VL was more permissive (p. 4, 2nd and 3rd paragraphs). However, when CDR regions were switched between variable domains, it was found that for the VH binding to antigen not only the CDRs but framework regions were also a determining factor (p 9, 6th paragraph). It was found, “Hence, complex formation of the VL and VH domains appears to lock some of the antigen binding loops into distinct conformations.” (p. 11, first paragraph) It was discussed that (p. 11, start of 3rd paragraph), “The relationship between structure, stability and binding affinity of VH and VL is still unclear. This is an important aspect for understanding antibody architecture both as the basis of our immune system and also in the context of the engineering of antibodies for therapeutic purposes. In this context, it was found that in mutants an increase in affinity is often accompanied by a decrease in stability and vice versa - and these consequences are difficult to predict33–39.” Further (p. 13, start of last paragraph), “It seems that during antibody biogenesis the effect of CDRs on the stability of VH domains is a decisive, so far underappreciated factor…. The grafting constructs revealed that CDRs, in addition to antigen binding, affect variable domain structure strongly.” It is reported previous studies using CDR grafting for antibody humanization showed the importance of framework residues in the context of antigen binding and stability (p. 14, 1st paragraph). The reference concludes (p. 14, end of 2nd paragraph and 3rd paragraph), “[B]inding to the antigen is affected by each CDR loop differently and changes in loop mobility can in principle affect antigen binding affinity in an unpredictable way. (¶) Taken together our data indicate that multiple determinants regulate the VH/VL association and the affinity for the antigen. The interplay between interface interactions and CDRs turned out to be complex with mutual influences on VH/VL association and antigen binding.” The specification provides no guidance or direction for placing the CDRs of claim 14 in a scaffold other than the respective VH and VL disclosed in the specification (SEQ ID NO:13/15 and 14/26) to allow the antibody to be used, particularly as a therapeutic at the claimed dosages and administration frequency.
Further, the specification does not disclose that VH and VL from different antibodies, such as the VH of SEQ ID NO:13 with VL of SEQ ID NO16, could pair to bind PD-L1 with an affinity sufficient for use. The prior art does not support the reasonable expectation of successfully making a functional antibody or antigen-binding fragment thereof under these circumstances. For example, as shown by Kranz et al., (Proc. Natl. Acad. Sci., USA, 78(9):5807-5811, 1981; p. 5809, col. 1, first part of second paragraph) mixing heavy and light chains from six monoclonal anti-fluorescyl antibodies, heterologous heavy and light chain mixtures did not form anti-fluorescyl active sites. In another experiment Kraz et al. found (supra, p. 5809, col. 1, third paragraph), “Of the 30 possible heterologous H and L chain combinations, 13 did not reassociate within detectable limits…, 13 reassociated but with less affinity than the homologous association,.. and 4 associated with greater affinity than the homologous reassociation….” As discussed above, it has been shown that the pairing of variable heavy and light chain regions is not random, and only specific pairs of VH and VL bind a designated antigen. Herold et al. (Scientific Reports, 7:12276, DOI:10.1038/s41598-017-12519-9, Sept. 2017, cited in the IDS filed 4/25/2024) showed by mutating conserved regions of VH and VL, almost all VH mutants led to decreased antigen-binding affinity, while the VL was more permissive (p. 4, 2nd and 3rd paragraphs). However, when CDR regions were switched between variable domains, it was found that for the VH binding to antigen not only the CDRs but framework regions were also a determining factor (p 9, 6th paragraph). Herold et al. concludes (p. 14, end of 2nd paragraph and 3rd paragraph), “[B]inding to the antigen is affected by each CDR loop differently and changes in loop mobility can in principle affect antigen binding affinity in an unpredictable way. (¶) Taken together our data indicate that multiple determinants regulate the VH/VL association and the affinity for the antigen. The interplay between interface interactions and CDRs turned out to be complex with mutual influences on VH/VL association and antigen binding.”
It is stated in AbbVie Deustschland GmbH y. Janssen Biotechnology, Ltd., 111 USPQ 1780, 1789 (759 F.3d 1285, 1298), (Fed. Cir. 2014) discussing Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005) that “When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed results and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus." Again in AbbVie at 1788, reiterating Enzo Biochem., Inc., 323 F.3d at 964 (Fed. Cir. 2002), “It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date...” This is not the case for an antibody which binds PD-L1, for which aside from the disclosed CDR-H1-3 with CDR-L1-3 of antibody 5G11 or, separately, 13C5, there is no reasonable structure-function correlation established. PD-L1 antibodies which are encompassed by those with the recited amount of identity or variation (e.g., claims 14 and 34) are not required to have any particular conserved structure that is responsible for the required function. Also, mixing-and-matching of antibody regions throws the regions out of structural context and so removes the native structure-function correlation.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
With the exception of the anti-PD-L1 antibody having the sequences referred to above, i.e., those belonging solely to 5G11 or solely to 13C5, the skilled artisan cannot envision the detailed chemical structure of the encompassed antibodies and antigen-binding fragments thereof, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
Therefore, only antibody that binds PD-L1 and comprises CDR-H1-3 of SEQ ID NO:1-3 and CDR-L1-3 of SEQ ID NO:7-9 or SEQ ID NO:4-6 and SEQ ID NO:10-12 for claims 14-17, 20, 23, 32-36, 39 and 41, and comprises the VH is SEQ ID NO:13 and VL is SEQ ID NO:15 or VH is SEQ ID NO:14 and VL is SEQ ID NO:16, respectively, for claims 18, 19, 21, 22, 37, 38 and 40, or the heavy chain (HC) comprises SEQ ID NO:17 or 21 and light chain (LC) comprises SEQ ID NO:18 or SEQ ID NO:19 and 21, respectively, but not the full breadth of the claim meets the written description provision of 35 U.S.C. § 112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Priority
Applicant cannot rely upon the certified copy of the foreign priority application (CN202010814874.6) to overcome this rejection because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216.
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.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 14 -23, 32-37 and 38-41 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2016/022630 A1 (Zha, cited in the IDs filed 11/07/2024), Shen et al., (J. Hematol. Oncol. 11:120, 11 pages, 2018) and ClinicalTrial.gov Study NCT03996408 (https://clinicaltrials.gov/study/NCT03996408?intr=pd-l1%20and%20(anlotinib%20OR%20AR3181%20OR%20AR-3181)%20&viewType=Table&limit=50&page=1&rank=7&tab=history&a=1#version-content-panel, 21 Jun. 2019).
WO 2016/022630 (Zha) teaches treatment of cancer by administration of an anti-human PD-L1 antibody (Example 1 and [0087]), including liposarcoma, angiosarcoma, endothelial sarcoma, leimyosarcoma, lymphangiosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, rhabdomyosarcoma, fibrosarcoma and myxosarcoma ([0089]). The antibody may be administered with an additional therapeutic agent and administration may be concurrent or sequential. They may be formulated separately or administered in the same formulation (([0095]). Anti-PD-L1 antibodies hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1are taught, including their sequences, heavy and light chain CDR1-3 of SEQ ID NO: 81-85 (5G11) and 93-98 (13C5) ([0109]), comprised by the humanized (hu) heavy and light chain variable regions (VH/VL) of SEQ ID NO:42/44 and 46/48, respectively (see also claim 5). Heavy chain of hu5G11-IgG1 and -IgG4 are SEQ ID NO:70 and 72, respectively, and light chain is SEQ ID NO:74. The heavy chain of hu13C5-IgG1 and -IgG4 are SEQ ID NO:76 and 78, respectively, and light chain is SEQ ID NO:80 ([0110]). The antibodies block binding of PD-L1 to PD-1 ([0116]). They also induced secretion of IFN-γ and IL-2 in mixed lymphocyte cultures and also reduced the inhibitory effect of T regulatory cells on secretion of IFN-γ by T effector cells ([0118]-[0119]). They enhanced IFN-γ secretion by T cells ([0120]). Zha does not teach treatment with anlotinib or dosing amounts of frequencies.
Shen et al. discusses the clinical use of anlotinib, which is an oral receptor tyrosine kinase (RTK) inhibitor taken orally that targets multiple RTKs (Fig. 1 and p. 2/11, col. 1, third paragraph). Its antiangiogenic activity is stronger than 3 other such drugs, including sunitinib, sorafenib and ninetedanib (p. 2/11, start of col. 2). As discussed on p. 4/11, col. 1, second and third full paragraph, a phase I study showed that anlotinib caused tumor shrinkage in soft tissue sarcomas (STSs). This led to a single-arm phase II study in patients with advanced STS, including fibrous histocytoma, liposarcoma, leiomysarcoma, synovial sarcoma and others, who failed previous conventional treatment. For the phase II study, “Overall, anlotinib demonstrated better clinical benefits in many pathological types of STS.” A related phase IIb study in patients with advance STS who were treatment-intolerant or progressed on anthracycline-based chemotherapy showed overall response rate (ORR) and disease control rate (DCR) that was significantly higher than in the control group. “This trial further confirmed the efficacy and safety of anlotinib in advanced STS [44].” Based on clinical findings, the recommended dosing has been 12 mg daily for 2 weeks, followed by a 1-week break (p. 3/11, end of col. 1 and first paragraph of col. 2). There are ongoing clinical trials evaluating anlotinib in several STS subtypes, including leiomyosarcoma and synovial sarcoma (p. 7/11, col. 2, second full paragraph, also Table 3). It is concluded (p. 7/11, last paragraph), “Anlotinib has exceptional efficacy and acceptable toxicity for the treatment of advanced NSCLC [non-small cell lung cancer] and STS.”
NCT03996408 is a clinical trial designed to treat advanced cholangiocarcinoma by administration with humanized anti-PD-L1 antibody TQB2450 with anlotinib (Official Title). TQB2450 blocked binding of PD-L1 to PD-1 and restores T cell activity (Arms and Interventions: Assigned Interventions). The antibody is administered at a dose of 1200 mg intravenously on day 1 of each 21-day cycle plus anlotinib capsule given orally one a day for the first 14 days of the cycle followed by a 7 day break (Arms and Interventions:Arms).
It would have been obvious to the artisan of ordinary skill before the effective filing date of the instant invention to treated a STS by the method of NCT03996408 wherein humanized anti-PD-L1 antibody hu5G11 or hu13C5 was substituted to TQB2450 because all antibodies were shown to bind PD-L1, block its binding to PD-1 and increase T cell activity, e.g., IFN-γ secretion, for the treatment of a cancer, including a STS. Because both Zha and Shen teach the anti-PD-L1 antibody and anlotinib were useful for treatment of STSs, e.g., leimyosarcoma, and had the same activities as the agents in NCT03996408, one would have had a reasonable expectation of success. It would have been obvious wherein the dosing regimen of the humanized anti-human PD-L1 antibody of Zha and anlotinib was as set forth in NCT03996408 and Shen et al., i.e., antibody administered at a dose of 1200 mg intravenously on day 1 of each 21-day cycle plus 12 mg anlotinib capsule given orally one a day for the first 14 days of the cycle followed by a 7 day break. Those doses inherently result in a weight ratio of anti-PD-L1 antibody 5G11 or 13C5 and anlotinib of (0.35-29):1, (3.5-29):1, (3.5- 14.5):1 or (7-14.5):1. Because the two agents are administered to the same patient in a particular treatment regimen, it would have been obvious wherein they were in a kit comprising instructions for their use in STS. The sequences of hu5G11 and hu13C5 of Zha are the same as those of the instant claims.
Claim(s) 14-23 and 32-41 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/239085 A1 (Yang; cited in the IDS filed 02/09/2023, translation attached as an appendix to this Office action) in view of WO 2016/022630 A1 (Zha, cited in the IDs filed 11/07/2024) and Shen et al. (J. Hematol. Oncol. 11:120, 11 pages, 2018).
WO 2020/239085 (Yang) teaches treatment of melanoma with the anti-PD-L1 antibody hu13V5-hIgG1 and -hIgG4 and 5G11-hIgG1 having the sequences of HCDR1-3 of SEQ ID NO:1-3 and 4-6 and LCDR1-3 of SEQ ID NO:7-9 and 10-12, respectively, and variable heavy and light chain regions of SEQ ID NO:13/15 and 14/16, respectively (p. 6, last full paragraph; [0010] of translation). The amount of antibody administered is 600-2400 mg and amount of anlotinib is 84-168 mg, with a treatment cycle that may be 21 days (claim 6). More specifically, a pharmaceutical composition comprising 6, 8, 10 or 12 mg anlotinib and 600-2400 mg anti-PD-L1 is taught in claim 4. The weight ratio of the anti-PD-L1 antibody and anlotinib is (0.35-29):1, (3.5-29):1, (3.5- 14.5):1 or (7-14.5):1 (claim 5). Administration of the antibody and anlotinib may be simultaneous or sequential (claim 9). In the example, patients were given 10 cycles, 21 days each, of 1200 mg anti-PD-L1 antibody hu5G11-hG1 by injection and 12 mg oral anlotinib (capsule form, section 1.2 of p. 11 through 1.5 of p. 12; [0160], [0171]-[0173] of translation). It is taught that anlotinib can be administered daily on days 1-14 of each 21-day cycle, while the antibody is administered only on the first day (p. 3, last third, [0043]-[0045] of translation). A pharmaceutical composition comprising the anti-PD-L1 antibody may have an antibody concentration of 10-60 mg/ml (p. 4, third paragraph; [0051] translation). A kit is claimed comprising a combination of anti-PD-L1 antibody and anlotinib (claims 5 and 12-18). Yang does not teach treatment of soft tissue sarcoma with the disclosed method.
Zha teaches treatment of cancer by administration of an anti-human PD-L1 antibody (Example 1 and [0087]), including liposarcoma, antiosarcoma, endothelial sarcoma, leimyosarcoma, lymphangiosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, rhabdomyosarcoma, fibrosarcoma and myxosarcoma ([0089]). The antibody may be administered with an additional therapeutic agent and administration may be concurrent or sequential. They may be formulated separately or administered in the same formulation (([0095]). Anti-PD-L1 antibodies hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1are taught, including their sequences, heavy and light chain CDR1-3 of SEQ ID NO: 81-85 (5G11) and 93-98 (13C5) ([0109]), comprised by the humanized (hu) heavy and light chain variable regions (VH/VL) of SEQ ID NO:42/44 and 46/48, respectively (see also claim 5). Heavy chain of hu5G11-IgG1 and -IgG4 are SEQ ID NO:70 and 72, respectively, and light chain is SEQ ID NO:74. The heavy chain of hu13C5-IgG1 and -IgG4 are SEQ ID NO:76 and 78, respectively, and light chain is SEQ ID NO:80 ([0110]).
Shen et al. discusses the clinical use of anlotinib, which is an oral receptor tyrosine kinase (RTK) inhibitor taken orally that targets multiple RTKs (Fig. 1 and p. 2/11, col. 1, third paragraph). Its antiangiogenic activity is stronger than 3 other such drugs, including sunitinib, sorafenib and ninetedanib (p. 2/11, start of col. 2). As discussed on p. 4/11, col. 1, second and third full paragraph, a phase I study showed that anlotinib caused tumor shrinkage in soft tissue sarcomas (STSs). This led to a single-arm phase II study in patients with advanced STS, including fibrous histocytoma, liposarcoma, leiomysarcoma, synovial sarcoma and others, who failed previous conventional treatment. For the phase II study, “Overall, anlotinib demonstrated better clinical benefits in many pathological types of STS.” A related phase IIb study in patients with advance STS who were treatment-intolerant or progressed on anthracycline-based chemotherapy showed overall response rate (ORR) and disease control rate (DCR) that was significantly higher than in the control group. “This trial further confirmed the efficacy and safety of anlotinib in advanced STS [44].” Based on clinical findings, the recommended dosing has been 12 mg daily for 2 weeks, followed by a 1-week break (p. 3/11, end of col. 1 and first paragraph of col. 2). There are ongoing clinical trials evaluating anlotinib in several STS subtypes, including leiomyosarcoma and synovial sarcoma (p. 7/11, col. 2, second full paragraph, also Table 3). It is concluded (p. 7/11, last paragraph), “Anlotinib has exceptional efficacy and acceptable toxicity for the treatment of advanced NSCLC [non-small cell lung cancer] and STS.”
It would have been obvious to the artisan of ordinary skill before the effective filing date of the instant invention to have treated an STS by the method of Yang because both Zha and Shen teach the anti-PD-L1 antibody and anlotinib were useful for treatment of STSs, e.g., leimyosarcoma. The antibodies of Zha have sequences identical to those of Yang and are the same as those of the instant claims.
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.
A) Claims 14-23 and 32-41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 20-25 and 28-34 of copending Application No. 17/438,804 (‘804) in view of WO 2016/022630 A1 (Zha, cited in the IDs filed 11/07/2024) and Shen et al., (J. Hematol. Oncol. 11:120, 11 pages, 2018)
The claims of the instant and copending application are both drawn to a method of treating a cancer in a subject by administration of an antibody that binds PD-L1 and anlotinib. Both applications recite in the claims the same anti-PD-L1 antibody, having the 6 CDRs and the VH/VL of hu13C5 or hu5G11. They recite the same doses and administration schedule, including 600-2400 mg anti-PD-L1 and 6, 8, 10 and/or 12 mg anlotinib, as well as a pharmaceutical composition comprising 600-2400 mg anti-PD-L1 antibody and 84-168 mg anlotinib. Administration is claimed as anlotinib administered on days 1-14 of each 3-week cycle and antibody is administered on day 1 of the cycle.
The difference between the applications is that the instant claims are drawn to treatment of soft tissue sarcoma (STS) and claims of ‘804 are drawn to treatment of small cell lung cancer.
Zha teaches treatment of cancer by administration of an anti-human PD-L1 antibody (Example 1 and [0087]), including liposarcoma, angiosarcoma, endothelial sarcoma, leimyosarcoma, lymphangiosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, rhabdomyosarcoma, fibrosarcoma and myxosarcoma ([0089]). The antibody may be administered with an additional therapeutic agent and administration may be concurrent or sequential. They may be formulated separately or administered in the same formulation (([0095]). Anti-PD-L1 antibodies hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1are taught, including their sequences, heavy and light chain CDR1-3 of SEQ ID NO: 81-85 (5G11) and 93-98 (13C5) ([0109]), comprised by the humanized (hu) heavy and light chain variable regions (VH/VL) of SEQ ID NO:42/44 and 46/48, respectively (see also claim 5). Heavy chain of hu5G11-IgG1 and -IgG4 are SEQ ID NO:70 and 72, respectively, and light chain is SEQ ID NO:74. The heavy chain of hu13C5-IgG1 and -IgG4 are SEQ ID NO:76 and 78, respectively, and light chain is SEQ ID NO:80 ([0110]). The antibodies block binding of PD-L1 to PD-1 ([0116]). They also induced secretion of IFN-γ and IL-2 in mixed lymphocyte cultures and also reduced the inhibitory effect of T regulatory cells on secretion of IFN-γ by T effector cells ([0118]-[0119]). They enhanced IFN-γ secretion by T cells ([0120]).
Shen et al. discusses the clinical use of anlotinib, which is an oral receptor tyrosine kinase (RTK) inhibitor taken orally that targets multiple RTKs (Fig. 1 and p. 2/11, col. 1, third paragraph). Its antiangiogenic activity is stronger than 3 other such drugs, including sunitinib, sorafenib and ninetedanib (p. 2/11, start of col. 2). As discussed on p. 4/11, col. 1, second and third full paragraph, a phase I study showed that anlotinib caused tumor shrinkage in soft tissue sarcomas (STSs). This led to a single-arm phase II study in patients with advanced STS, including fibrous histocytoma, liposarcoma, leiomysarcoma, synovial sarcoma and others, who failed previous conventional treatment. For the phase II study, “Overall, anlotinib demonstrated better clinical benefits in many pathological types of STS.” A related phase IIb study in patients with advance STS who were treatment-intolerant or progressed on anthracycline-based chemotherapy showed overall response rate (ORR) and disease control rate (DCR) that was significantly higher than in the control group. “This trial further confirmed the efficacy and safety of anlotinib in advanced STS [44].” Based on clinical findings, the recommended dosing has been 12 mg daily for 2 weeks, followed by a 1-week break (p. 3/11, end of col. 1 and first paragraph of col. 2). There are ongoing clinical trials evaluating anlotinib in several STS subtypes, including leiomyosarcoma and synovial sarcoma (p. 7/11, col. 2, second full paragraph, also Table 3). It is concluded (p. 7/11, last paragraph), “Anlotinib has exceptional efficacy and acceptable toxicity for the treatment of advanced NSCLC [non-small cell lung cancer] and STS.”
It would have been obvious to treat STS with the method of ‘804 in view of the prior art teaching of the applicability of the anti-PD-L1 antibody and anlotinib in the treatment of STS.
This is a provisional nonstatutory double patenting rejection.
Note application ‘804 has been allowed and the rejection will be nonprovisional once it issues as a patent.
B) Claims14-23 and 32-41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10, 15 and 19-31 of copending Application No. 17/595,519 (‘519) in view of WO 2020/239085 A1 (Yang; cited in the IDS filed 02/09/2023, translation attached as an appendix to this Office action), WO 2016/022630 A1 (Zha, cited in the IDs filed 11/07/2024) and Shen et al. (J. Hematol. Oncol. 11:120, 11 pages, 2018).
The claims of the instant application are drawn to a method of treating a soft tissue sarcoma (STS) in a subject by administration of an antibody that binds PD-L1 and anlotinib. The anti-PD-L1 antibody has the 6 CDRs or the VH/VL of hu13C5 or hu5G11. The doses and administration schedule include 600-2400 mg anti-PD-L1 and 6, 8, 10 and/or 12 mg anlotinib, as well as a pharmaceutical composition comprising 600-2400 mg anti-PD-L1 antibody and 84-168 mg anlotinib. Anlotinib is administered on days 1-14 of each 3-week cycle and antibody is administered on day 1 of the cycle. Further claimed is a pharmaceutical composition having a concentration of 10-60 mg/mL anti-PD-L1 antibody.
The claims 17-18 of ‘519 are drawn to a method of treating head and neck cancer comprising administering compound I (1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropylamine hydrochloride; defined in the specification as anlotinib in the paragraph bridging pp. 16-17) and sintilimab, defined as an anti-PD-1 antibody (p. 13, second to last paragraph). Claims 22-24 recite anlotinib administered in a 21-day cycle of days 1-14 of treatment plus 1 week without (i.e., administration of 84-168 mg/cycle).
The claims of ‘519 differ from the instant claims in that they do not recite the same antibody or any dosages thereof and treatment is not of STS.
WO 2020/239085 (Yang) teaches treatment of melanoma with the anti-PD-L1 antibody hu13V5-hIgG1 and -hIgG4 and 5G11-hIgG1 having the sequences of HCDR1-3 of SEQ ID NO:1-3 and 4-6 and LCDR1-3 of SEQ ID NO:7-9 and 10-12, respectively, and variable heavy and light chain regions of SEQ ID NO:13/15 and 14/16, respectively (p. 6, last full paragraph; [0010] of translation). The amount of antibody administered is 600-2400 mg and amount of anlotinib is 84-168 mg, with a treatment cycle that may be 21 days (claim 6). More specifically, a pharmaceutical composition comprising 6, 8, 10 or 12 mg anlotinib and 600-2400 mg anti-PD-L1 is taught in claim 4. The weight ratio of the anti-PD-L1 antibody and anlotinb is (0.35-29):1, (3.5-29):1, (3.5- 14.5):1 or (7-14.5):1 (claim 5). Administration of the antibody and anlotinib may be simultaneous or sequential (claim 9). In the example, patients were give 10 cycles, 21 days each, of 1200 mg anti-PD-L1 antibody hu5G11-hG1 by injection and 12 mg oral anlotinib (capsul form, section 1.2 of p. 11 through 1.5 of p. 12; [0160], [0171]-[0173] of translation). It is taught that anlotinib can be administered daily on days 1-14 of each 21-day cycle, while the antibody is administered only on the first day (p. 3, last third, [0043]-[0045] of translation). A pharmaceutical composition comprising the anti-PD-L1 antibody may have an antibody concentration of 10-60 mg/ml (p. 4, third paragraph; [0051] translation). A kit is claimed comprising a combination of anti-PD-L1 antibody and anlotinib (claims 5 and 12-18).
Zha teaches treatment of cancer by administration of an anti-human PD-L1 antibody (Example 1 and [0087]), including liposarcoma, antiosarcoma, endothelial sarcoma, leimyosarcoma, lymphangiosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, rhabdomyosarcoma, fibrosarcoma and myxosarcoma ([0089]). The antibody may be administered with an additional therapeutic agent and administration may be concurrent or sequential. They may be formulated separately or administered in the same formulation (([0095]). Anti-PD-L1 antibodies hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1are taught, including their sequences, heavy and light chain CDR1-3 of SEQ ID NO: 81-85 (5G11) and 93-98 (13C5) ([0109]), comprised by the humanized (hu) heavy and light chain variable regions (VH/VL) of SEQ ID NO:42/44 and 46/48, respectively (see also claim 5). Heavy chain of hu5G11-IgG1 and -IgG4 are SEQ ID NO:70 and 72, respectively, and light chain is SEQ ID NO:74. The heavy chain of hu13C5-IgG1 and -IgG4 are SEQ ID NO:76 and 78, respectively, and light chain is SEQ ID NO:80 ([0110]).
Shen et al. discusses the clinical use of anlotinib, which is an oral receptor tyrosine kinase (RTK) inhibitor taken orally that targets multiple RTKs (Fig. 1 and p. 2/11, col. 1, third paragraph). Its antiangiogenic activity is stronger than 3 other such drugs, including sunitinib, sorafenib and ninetedanib (p. 2/11, start of col. 2). As discussed on p. 4/11, col. 1, second and third full paragraph, a phase I study showed that anlotinib caused tumor shrinkage in soft tissue sarcomas (STSs). This led to a single-arm phase II study in patients with advanced STS, including fibrous histocytoma, liposarcoma, leiomysarcoma, synovial sarcoma and others, who failed previous conventional treatment. For the phase II study, “Overall, anlotinib demonstrated better clinical benefits in many pathological types of STS.” A related phase IIb study in patients with advance STS who were treatment-intolerant or progressed on anthracycline-based chemotherapy showed overall response rate (ORR) and disease control rate (DCR) that was significantly higher than in the control group. “This trial further confirmed the efficacy and safety of anlotinib in advanced STS [44].” Based on clinical findings, the recommended dosing has been 12 mg daily for 2 weeks, followed by a 1-week break (p. 3/11, end of col. 1 and first paragraph of col. 2). There are ongoing clinical trials evaluating anlotinib in several STS subtypes, including leiomyosarcoma and synovial sarcoma (p. 7/11, col. 2, second full paragraph, also Table 3). It is concluded (p. 7/11, last paragraph), “Anlotinib has exceptional efficacy and acceptable toxicity for the treatment of advanced NSCLC [non-small cell lung cancer] and STS.”
It would have been obvious to treat STS with the method of ‘519, substituting anti-PD-L1 antibody hu5G11 or hu13C5 of Yang and Zha for sintilimab because both blocked the interaction of PD-L1 with PD-1 and were used to treat cancers. It would have been obvious to administer the anti-PD-L1 antibody in the dosage and in the regimen taught by Yang since that was for treatment of a cancer and the amounts of and timings of anlotinib were the same. It would have been obvious wherein the treatment was for STS, e.g., leimyosarcoma, in view of the prior art teachings thereof.
This is a provisional nonstatutory double patenting rejection.
C) Claims 14-23 and 32-41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 17-24 and 31-34 of copending Application No. 17/613,332 (‘332) in view of WO 2020/239085 A1 (Yang; cited in the IDS filed 02/09/2023, translation attached as an appendix to this Office action), WO 2016/022630 A1 (Zha, cited in the IDs filed 11/07/2024) and Shen et al. (J. Hematol. Oncol. 11:120, 11 pages, 2018).
The claims of the instant application are drawn to a method of treating a soft tissue sarcoma (STS) in a subject by administration of an antibody that binds PD-L1 and anlotinib. The anti-PD-L1 antibody has the 6 CDRs or the VH/VL of hu13C5 or hu5G11. The doses and administration schedule include 600-2400 mg anti-PD-L1 and 6, 8, 10 and/or 12 mg anlotinib, as well as a pharmaceutical composition comprising 600-2400 mg anti-PD-L1 antibody and 84-168 mg anlotinib. Anlotinib is administered on days 1-14 of each 3-week cycle and antibody is administered on day 1 of the cycle. Further claimed is a pharmaceutical composition having a concentration of 10-60 mg/mL anti-PD-L1 antibody.
The claims 17-18 of ‘332 are drawn to a method of treating head and neck cancer comprising administering compound I (1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropylamine hydrochloride; defined in the specification as anlotinib in the paragraph bridging pp. 16-17) and sintilimab, defined as an anti-PD-1 antibody (p. 13, second to last paragraph). Claims 31-34 recite anlotinib administered in a 21-day cycle of days 1-14 of treatment plus 1 week without (i.e., administration of 84-168 mg/cycle).
The claims of ‘332 differ from the instant claims in that they do not recite the same antibody or any dosages thereof and treatment is not of STS.
WO 2020/239085 (Yang) teaches treatment of melanoma with the anti-PD-L1 antibody hu13V5-hIgG1 and -hIgG4 and 5G11-hIgG1 having the sequences of HCDR1-3 of SEQ ID NO:1-3 and 4-6 and LCDR1-3 of SEQ ID NO:7-9 and 10-12, respectively, and variable heavy and light chain regions of SEQ ID NO:13/15 and 14/16, respectively (p. 6, last full paragraph; [0010] of translation). The amount of antibody administered is 600-2400 mg and amount of anlotinib is 84-168 mg, with a treatment cycle that may be 21 days (claim 6). More specifically, a pharmaceutical composition comprising 6, 8, 10 or 12 mg anlotinib and 600-2400 mg anti-PD-L1 is taught in claim 4. The weight ratio of the anti-PD-L1 antibody and anlotinb is (0.35-29):1, (3.5-29):1, (3.5- 14.5):1 or (7-14.5):1 (claim 5). Administration of the antibody and anlotinib may be simultaneous or sequential (claim 9). In the example, patients were give 10 cycles, 21 days each, of 1200 mg anti-PD-L1 antibody hu5G11-hG1 by injection and 12 mg oral anlotinib (capsul form, section 1.2 of p. 11 through 1.5 of p. 12; [0160], [0171]-[0173] of translation). It is taught that anlotinib can be administered daily on days 1-14 of each 21-day cycle, while the antibody is administered only on the first day (p. 3, last third, [0043]-[0045] of translation). A pharmaceutical composition comprising the anti-PD-L1 antibody may have an antibody concentration of 10-60 mg/ml (p. 4, third paragraph; [0051] translation). A kit is claimed comprising a combination of anti-PD-L1 antibody and anlotinib (claims 5 and 12-18).
Zha teaches treatment of cancer by administration of an anti-human PD-L1 antibody (Example 1 and [0087]), including liposarcoma, antiosarcoma, endothelial sarcoma, leimyosarcoma, lymphangiosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, rhabdomyosarcoma, fibrosarcoma and myxosarcoma ([0089]). The antibody may be administered with an additional therapeutic agent and administration may be concurrent or sequential. They may be formulated separately or administered in the same formulation (([0095]). Anti-PD-L1 antibodies hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1are taught, including their sequences, heavy and light chain CDR1-3 of SEQ ID NO: 81-85 (5G11) and 93-98 (13C5) ([0109]), comprised by the humanized (hu) heavy and light chain variable regions (VH/VL) of SEQ ID NO:42/44 and 46/48, respectively (see also claim 5). Heavy chain of hu5G11-IgG1 and -IgG4 are SEQ ID NO:70 and 72, respectively, and light chain is SEQ ID NO:74. The heavy chain of hu13C5-IgG1 and -IgG4 are SEQ ID NO:76 and 78, respectively, and light chain is SEQ ID NO:80 ([0110]).
Shen et al. discusses the clinical use of anlotinib, which is an oral receptor tyrosine kinase (RTK) inhibitor taken orally that targets multiple RTKs (Fig. 1 and p. 2/11, col. 1, third paragraph). Its antiangiogenic activity is stronger than 3 other such drugs, including sunitinib, sorafenib and ninetedanib (p. 2/11, start of col. 2). As discussed on p. 4/11, col. 1, second and third full paragraph, a phase I study showed that anlotinib caused tumor shrinkage in soft tissue sarcomas (STSs). This led to a single-arm phase II study in patients with advanced STS, including fibrous histocytoma, liposarcoma, leiomysarcoma, synovial sarcoma and others, who failed previous conventional treatment. For the phase II study, “Overall, anlotinib demonstrated better clinical benefits in many pathological types of STS.” A related phase IIb study in patients with advance STS who were treatment-intolerant or progressed on anthracycline-based chemotherapy showed overall response rate (ORR) and disease control rate (DCR) that was significantly higher than in the control group. “This trial further confirmed the efficacy and safety of anlotinib in advanced STS [44].” Based on clinical findings, the recommended dosing has been 12 mg daily for 2 weeks, followed by a 1-week break (p. 3/11, end of col. 1 and first paragraph of col. 2). There are ongoing clinical trials evaluating anlotinib in several STS subtypes, including leiomyosarcoma and synovial sarcoma (p. 7/11, col. 2, second full paragraph, also Table 3). It is concluded (p. 7/11, last paragraph), “Anlotinib has exceptional efficacy and acceptable toxicity for the treatment of advanced NSCLC [non-small cell lung cancer] and STS.”
It would have been obvious to treat STS with the method of ‘332, substituting anti-PD-L1 antibody hu5G11 or hu13C5 of Yang and Zha for sintilimab because both blocked the interaction of PD-L1 with PD-1 and were used to treat cancers. It would have been obvious to administer the anti-PD-L1 antibody in the dosage and in the regimen taught by Yang since that was for treatment of a cancer and the amounts of and timings of anlotinib were the same. It would have been obvious wherein the treatment was for STS, e.g., leimyosarcoma, in view of the prior art teachings thereof.
This is a provisional nonstatutory double patenting rejection.
D) Claims 14-23 and 32-41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 22-24, 30-41 of copending Application No. 17/773,723 (‘723) in view of WO 2020/239085 A1 (Yang; cited in the IDS filed 02/09/2023, translation attached as an appendix to this Office action), WO 2016/022630 A1 (Zha, cited in the IDs filed 11/07/2024) and Shen et al. (J. Hematol. Oncol. 11:120, 11 pages, 2018).
The claims of the instant application are drawn to a method of treating a soft tissue sarcoma (STS) in a subject by administration of an antibody that binds PD-L1 and anlotinib. The anti-PD-L1 antibody has the 6 CDRs or the VH/VL of hu13C5 or hu5G11. The doses and administration schedule include 600-2400 mg anti-PD-L1 and 6, 8, 10 and/or 12 mg anlotinib, as well as a pharmaceutical composition comprising 600-2400 mg anti-PD-L1 antibody and 84-168 mg anlotinib. Anlotinib is administered on days 1-14 of each 3-week cycle and antibody is administered on day 1 of the cycle. Further claimed is a pharmaceutical composition having a concentration of 10-60 mg/mL anti-PD-L1 antibody.
The claims 22-24 of ‘723 are drawn to a method of endometrial cancer comprising administering compound I, 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropylamine hydrochloride (defined in the specification as anlotinib in the paragraph bridging p. 19, lines 1-6) and an anti-PD-1 antibody. Claims 32-33 and 41 recite anlotinib administered in a 21-day cycle of days 1-14 of treatment plus 1 week without in 84-168 mg/cycle. The antibody is administered on the first day of the 21-day cycle.
The claims of ‘723 differ from the instant claims in that they do not recite the same antibody or any dosages thereof and treatment is not of STS.
WO 2020/239085 (Yang) teaches treatment of melanoma with the anti-PD-L1 antibody hu13V5-hIgG1 and -hIgG4 and 5G11-hIgG1 having the sequences of HCDR1-3 of SEQ ID NO:1-3 and 4-6 and LCDR1-3 of SEQ ID NO:7-9 and 10-12, respectively, and variable heavy and light chain regions of SEQ ID NO:13/15 and 14/16, respectively (p. 6, last full paragraph; [0010] of translation). The amount of antibody administered is 600-2400 mg and amount of anlotinib is 84-168 mg, with a treatment cycle that may be 21 days (claim 6). More specifically, a pharmaceutical composition comprising 6, 8, 10 or 12 mg anlotinib and 600-2400 mg anti-PD-L1 is taught in claim 4. The weight ratio of the anti-PD-L1 antibody and anlotinb is (0.35-29):1, (3.5-29):1, (3.5- 14.5):1 or (7-14.5):1 (claim 5). Administration of the antibody and anlotinib may be simultaneous or sequential (claim 9). In the example, patients were give 10 cycles, 21 days each, of 1200 mg anti-PD-L1 antibody hu5G11-hG1 by injection and 12 mg oral anlotinib (capsul form, section 1.2 of p. 11 through 1.5 of p. 12; [0160], [0171]-[0173] of translation). It is taught that anlotinib can be administered daily on days 1-14 of each 21-day cycle, while the antibody is administered only on the first day (p. 3, last third, [0043]-[0045] of translation). A pharmaceutical composition comprising the anti-PD-L1 antibody may have an antibody concentration of 10-60 mg/ml (p. 4, third paragraph; [0051] translation). A kit is claimed comprising a combination of anti-PD-L1 antibody and anlotinib (claims 5 and 12-18).
Zha teaches treatment of cancer by administration of an anti-human PD-L1 antibody (Example 1 and [0087]), including liposarcoma, antiosarcoma, endothelial sarcoma, leimyosarcoma, lymphangiosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, rhabdomyosarcoma, fibrosarcoma and myxosarcoma ([0089]). The antibody may be administered with an additional therapeutic agent and administration may be concurrent or sequential. They may be formulated separately or administered in the same formulation (([0095]). Anti-PD-L1 antibodies hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1are taught, including their sequences, heavy and light chain CDR1-3 of SEQ ID NO: 81-85 (5G11) and 93-98 (13C5) ([0109]), comprised by the humanized (hu) heavy and light chain variable regions (VH/VL) of SEQ ID NO:42/44 and 46/48, respectively (see also claim 5). Heavy chain of hu5G11-IgG1 and -IgG4 are SEQ ID NO:70 and 72, respectively, and light chain is SEQ ID NO:74. The heavy chain of hu13C5-IgG1 and -IgG4 are SEQ ID NO:76 and 78, respectively, and light chain is SEQ ID NO:80 ([0110]).
Shen et al. discusses the clinical use of anlotinib, which is an oral receptor tyrosine kinase (RTK) inhibitor taken orally that targets multiple RTKs (Fig. 1 and p. 2/11, col. 1, third paragraph). Its antiangiogenic activity is stronger than 3 other such drugs, including sunitinib, sorafenib and ninetedanib (p. 2/11, start of col. 2). As discussed on p. 4/11, col. 1, second and third full paragraph, a phase I study showed that anlotinib caused tumor shrinkage in soft tissue sarcomas (STSs). This led to a single-arm phase II study in patients with advanced STS, including fibrous histocytoma, liposarcoma, leiomysarcoma, synovial sarcoma and others, who failed previous conventional treatment. For the phase II study, “Overall, anlotinib demonstrated better clinical benefits in many pathological types of STS.” A related phase IIb study in patients with advance STS who were treatment-intolerant or progressed on anthracycline-based chemotherapy showed overall response rate (ORR) and disease control rate (DCR) that was significantly higher than in the control group. “This trial further confirmed the efficacy and safety of anlotinib in advanced STS [44].” Based on clinical findings, the recommended dosing has been 12 mg daily for 2 weeks, followed by a 1-week break (p. 3/11, end of col. 1 and first paragraph of col. 2). There are ongoing clinical trials evaluating anlotinib in several STS subtypes, including leiomyosarcoma and synovial sarcoma (p. 7/11, col. 2, second full paragraph, also Table 3). It is concluded (p. 7/11, last paragraph), “Anlotinib has exceptional efficacy and acceptable toxicity for the treatment of advanced NSCLC [non-small cell lung cancer] and STS.”
It would have been obvious to treat STS with the method of ‘723, substituting anti-PD-L1 antibody hu5G11 or hu13C5 of Yang and Zha for the anti-PD-1 because both blocked the interaction of PD-L1 with PD-1 and were used to treat cancers. It would have been obvious to administer the anti-PD-L1 antibody in the dosage and in the regimen taught by Yang since that was for treatment of a cancer and the amounts of and timings of anlotinib were the same. It would have been obvious wherein the treatment was for STS, e.g., leimyosarcoma, in view of the prior art teachings thereof.
This is a provisional nonstatutory double patenting rejection.
E) Claims 14-23 and 32-41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 33-41 of copending Application No. 17/997,444 (‘444) in view of WO 2016/022630 A1 (Zha, cited in the IDs filed 11/07/2024) and Shen et al., (J. Hematol. Oncol. 11:120, 11 pages, 2018).
The claims of the instant and copending application are both drawn to a method of treating a cancer in a subject by administration of an antibody that binds PD-L1 and anlotinib. Both applications recite in the claims the same anti-PD-L1 antibody, having the 6 CDRs or the VH/VL of hu13C5 or hu5G11. They recite the same doses and administration schedule, including 1200 mg anti-PD-L1 and 6, 8, 10 and/or 12 mg anlotinib. Administration is claimed as anlotinib administered on days 1-14 of each 3-week cycle and antibody is administered on day 1 of the cycle. A pharmaceutical combination comprises the anti-PD-L1 antibody and anlotinib in a weight ratio of (0.35-29):1, (3.5-29):1, (3.5-14.5):1, or (7-14.5):1 is recited in the claims of both.
The difference between the applications is that the instant claims are drawn to treatment of soft tissue sarcoma (STS) and claims of ‘444 are drawn to treatment of kidney cancer.
Zha teaches treatment of cancer by administration of an anti-human PD-L1 antibody (Example 1 and [0087]), including liposarcoma, angiosarcoma, endothelial sarcoma, leimyosarcoma, lymphangiosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, rhabdomyosarcoma, fibrosarcoma and myxosarcoma ([0089]). The antibody may be administered with an additional therapeutic agent and administration may be concurrent or sequential. They may be formulated separately or administered in the same formulation (([0095]). Anti-PD-L1 antibodies hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1are taught, including their sequences, heavy and light chain CDR1-3 of SEQ ID NO: 81-85 (5G11) and 93-98 (13C5) ([0109]), comprised by the humanized (hu) heavy and light chain variable regions (VH/VL) of SEQ ID NO:42/44 and 46/48, respectively (see also claim 5). Heavy chain of hu5G11-IgG1 and -IgG4 are SEQ ID NO:70 and 72, respectively, and light chain is SEQ ID NO:74. The heavy chain of hu13C5-IgG1 and -IgG4 are SEQ ID NO:76 and 78, respectively, and light chain is SEQ ID NO:80 ([0110]). The antibodies block binding of PD-L1 to PD-1 ([0116]). They also induced secretion of IFN-γ and IL-2 in mixed lymphocyte cultures and also reduced the inhibitory effect of T regulatory cells on secretion of IFN-γ by T effector cells ([0118]-[0119]). They enhanced IFN-γ secretion by T cells ([0120]).
Shen et al. discusses the clinical use of anlotinib, which is an oral receptor tyrosine kinase (RTK) inhibitor taken orally that targets multiple RTKs (Fig. 1 and p. 2/11, col. 1, third paragraph). Its antiangiogenic activity is stronger than 3 other such drugs, including sunitinib, sorafenib and ninetedanib (p. 2/11, start of col. 2). As discussed on p. 4/11, col. 1, second and third full paragraph, a phase I study showed that anlotinib caused tumor shrinkage in soft tissue sarcomas (STSs). This led to a single-arm phase II study in patients with advanced STS, including fibrous histocytoma, liposarcoma, leiomysarcoma, synovial sarcoma and others, who failed previous conventional treatment. For the phase II study, “Overall, anlotinib demonstrated better clinical benefits in many pathological types of STS.” A related phase IIb study in patients with advance STS who were treatment-intolerant or progressed on anthracycline-based chemotherapy showed overall response rate (ORR) and disease control rate (DCR) that was significantly higher than in the control group. “This trial further confirmed the efficacy and safety of anlotinib in advanced STS [44].” Based on clinical findings, the recommended dosing has been 12 mg daily for 2 weeks, followed by a 1-week break (p. 3/11, end of col. 1 and first paragraph of col. 2). There are ongoing clinical trials evaluating anlotinib in several STS subtypes, including leiomyosarcoma and synovial sarcoma (p. 7/11, col. 2, second full paragraph, also Table 3). It is concluded (p. 7/11, last paragraph), “Anlotinib has exceptional efficacy and acceptable toxicity for the treatment of advanced NSCLC [non-small cell lung cancer] and STS.”
It would have been obvious to treat STS with the method of ‘444 in view of the prior art teaching of the applicability of the anti-PD-L1 antibody and anlotinib in the treatment of STS.
This is a provisional nonstatutory double patenting rejection.
F) Claims 14-23 and 32-41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 18, 19, 22 and 24-40 of copending Application No. 18/003,718 (‘718) in view of Shen et al. (J. Hematol. Oncol. 11:120, 11 pages, 2018).
The claims of the instant and copending application are both drawn to a method of treating a cancer in a subject by administration of an antibody that binds PD-L1 and anlotinib. Both applications recite in the claims the same anti-PD-L1 antibody, having the 6 CDRs or least the VH/VL of hu13C5 or hu5G11. They recite the same doses and administration schedule, including 600-2400 mg anti-PD-L1 and 6, 8, 10 and/or 12 mg anlotinib, as well as a pharmaceutical composition comprising 600-2400 mg anti-PD-L1 antibody and 84-168 mg anlotinib. Administration is claimed as anlotinib administered on days 1-14 of each 3-week cycle and antibody is administered on day 1 of the cycle. Further claimed is a pharmaceutical composition having a concentration of 10-60 mg/mL anti-PD-L1 antibody.
The difference between the applications is that the instant claims are drawn to treatment of soft tissue sarcoma (STS). Independent claim 18 of ‘718 is drawn to treatment of endometrial cancer. However, independent claim 31 of ‘718 is drawn to a method of treating a MSI-H and/or dMMM tumor with the same anti-PD-L1 antibody, including as specified in claim 32 wherein the tumor is a soft tissue sarcoma (STS), but administration of anlotinib is absent from the STS treatment claims.
Shen et al. discusses the clinical use of anlotinib, which is an oral receptor tyrosine kinase (RTK) inhibitor taken orally that targets multiple RTKs (Fig. 1 and p. 2/11, col. 1, third paragraph). Its antiangiogenic activity is stronger than 3 other such drugs, including sunitinib, sorafenib and ninetedanib (p. 2/11, start of col. 2). As discussed on p. 4/11, col. 1, second and third full paragraph, a phase I study showed that anlotinib caused tumor shrinkage in soft tissue sarcomas (STSs). This led to a single-arm phase II study in patients with advanced STS, including fibrous histocytoma, liposarcoma, leiomysarcoma, synovial sarcoma and others, who failed previous conventional treatment. For the phase II study, “Overall, anlotinib demonstrated better clinical benefits in many pathological types of STS.” A related phase IIb study in patients with advance STS who were treatment-intolerant or progressed on anthracycline-based chemotherapy showed overall response rate (ORR) and disease control rate (DCR) that was significantly higher than in the control group. “This trial further confirmed the efficacy and safety of anlotinib in advanced STS [44].” Based on clinical findings, the recommended dosing has been 12 mg daily for 2 weeks, followed by a 1-week break (p. 3/11, end of col. 1 and first paragraph of col. 2). There are ongoing clinical trials evaluating anlotinib in several STS subtypes, including leiomyosarcoma and synovial sarcoma (p. 7/11, col. 2, second full paragraph, also Table 3). It is concluded (p. 7/11, last paragraph), “Anlotinib has exceptional efficacy and acceptable toxicity for the treatment of advanced NSCLC [non-small cell lung cancer] and STS.”
Because the methods are identical in terms of agents used in the treatment and dosing amounts and regimen and all claims are drawn to a method of treating a cancer, and because ‘718 claims the antibody can be used to treat STS, it would have been obvious in view of Shen et al. to have used the method of claim 1 of ‘718 and dependent claims to treat STS.
This is a provisional nonstatutory double patenting rejection.
G) Claims 14-23 and 32-41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 49, 50, 53-61 and 65-68 of copending Application No. 18/292,655 (‘655) in view of WO 2016/022630 A1 (Zha, cited in the IDs filed 11/07/2024) and Shen et al., (J. Hematol. Oncol. 11:120, 11 pages, 2018)
The claims of the instant and copending application are both drawn to a method of treating a cancer in a subject by administration of an antibody that binds PD-L1 and anlotinib. Both applications recite in the claims the same anti-PD-L1 antibody, having the 6 CDRs or the VH/VL of hu13C5 or hu5G11. They recite the same doses and administration schedule, including 600-2400 mg anti-PD-L1 and 6, 8, 10 and/or 12 mg anlotinib, as well as a pharmaceutical composition comprising 600-2400 mg anti-PD-L1 antibody and 84-168 mg anlotinib. Administration is claimed as anlotinib administered on days 1-14 of each 3-week cycle and antibody is administered on day 1 of the cycle.
The difference between the applications is that the instant claims are drawn to treatment of soft tissue sarcoma (STS) and claims of ‘655 are drawn to treatment of small cell lung cancer and include treatment with a platinum-based anti-tumor drug and topoisomerase inhibitor. Claim 50 of ‘655 specifies a second treatment phase may be administration of only the anti-PD-L1 antibody and anlotinib.
Zha teaches treatment of cancer by administration of an anti-human PD-L1 antibody (Example 1 and [0087]), including liposarcoma, angiosarcoma, endothelial sarcoma, leimyosarcoma, lymphangiosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, rhabdomyosarcoma, fibrosarcoma and myxosarcoma ([0089]). The antibody may be administered with an additional therapeutic agent and administration may be concurrent or sequential. They may be formulated separately or administered in the same formulation (([0095]). Anti-PD-L1 antibodies hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1are taught, including their sequences, heavy and light chain CDR1-3 of SEQ ID NO: 81-85 (5G11) and 93-98 (13C5) ([0109]), comprised by the humanized (hu) heavy and light chain variable regions (VH/VL) of SEQ ID NO:42/44 and 46/48, respectively (see also claim 5). Heavy chain of hu5G11-IgG1 and -IgG4 are SEQ ID NO:70 and 72, respectively, and light chain is SEQ ID NO:74. The heavy chain of hu13C5-IgG1 and -IgG4 are SEQ ID NO:76 and 78, respectively, and light chain is SEQ ID NO:80 ([0110]). The antibodies block binding of PD-L1 to PD-1 ([0116]). They also induced secretion of IFN-γ and IL-2 in mixed lymphocyte cultures and also reduced the inhibitory effect of T regulatory cells on secretion of IFN-γ by T effector cells ([0118]-[0119]). They enhanced IFN-γ secretion by T cells ([0120]).
Shen et al. discusses the clinical use of anlotinib, which is an oral receptor tyrosine kinase (RTK) inhibitor taken orally that targets multiple RTKs (Fig. 1 and p. 2/11, col. 1, third paragraph). Its antiangiogenic activity is stronger than 3 other such drugs, including sunitinib, sorafenib and ninetedanib (p. 2/11, start of col. 2). As discussed on p. 4/11, col. 1, second and third full paragraph, a phase I study showed that anlotinib caused tumor shrinkage in soft tissue sarcomas (STSs). This led to a single-arm phase II study in patients with advanced STS, including fibrous histocytoma, liposarcoma, leiomysarcoma, synovial sarcoma and others, who failed previous conventional treatment. For the phase II study, “Overall, anlotinib demonstrated better clinical benefits in many pathological types of STS.” A related phase IIb study in patients with advance STS who were treatment-intolerant or progressed on anthracycline-based chemotherapy showed overall response rate (ORR) and disease control rate (DCR) that was significantly higher than in the control group. “This trial further confirmed the efficacy and safety of anlotinib in advanced STS [44].” Based on clinical findings, the recommended dosing has been 12 mg daily for 2 weeks, followed by a 1-week break (p. 3/11, end of col. 1 and first paragraph of col. 2). There are ongoing clinical trials evaluating anlotinib in several STS subtypes, including leiomyosarcoma and synovial sarcoma (p. 7/11, col. 2, second full paragraph, also Table 3). It is concluded (p. 7/11, last paragraph), “Anlotinib has exceptional efficacy and acceptable toxicity for the treatment of advanced NSCLC [non-small cell lung cancer] and STS.”
It would have been obvious to treat STS with the method of ‘655 with or without the additional therapeutics because ‘655 said a second treatment phase could be anti-PD-L1 antibody and anlotinib and in view of the prior art teaching of the applicability of the anti-PD-L1 antibody and anlotinib in the treatment of STS.
This is a provisional nonstatutory double patenting rejection.
H) Claims 14-23 and 32-41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. US 11,419,862 (‘862) in view of WO 2020/239085 A1 (Yang; cited in the IDS filed 02/09/2023, translation attached as an appendix to this Office action), WO 2016/022630 A1 (Zha, cited in the IDs filed 11/07/2024) and Shen et al. (J. Hematol. Oncol. 11:120, 11 pages, 2018).
The claims of the instant application are drawn to a method of treating a soft tissue sarcoma (STS) in a subject by administration of an antibody that binds PD-L1 and anlotinib. The anti-PD-L1 antibody has the 6 CDRs or the VH/VL of hu13C5 or hu5G11. The doses and administration schedule include 600-2400 mg anti-PD-L1 and 6, 8, 10 and/or 12 mg anlotinib, as well as a pharmaceutical composition comprising 600-2400 mg anti-PD-L1 antibody and 84-168 mg anlotinib. Anlotinib is administered on days 1-14 of each 3-week cycle and antibody is administered on day 1 of the cycle. Further claimed is a pharmaceutical composition having a concentration of 10-60 mg/mL anti-PD-L1 antibody.
The claims of ‘862 are drawn to treatment of advanced and/or metastatic and/or recurrent nasopharyngeal carcinoma by administration of the compound of formula I (claim 1, 1-((4-(4-fluoro-2-methyl-1h-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine as defined in col. 13, lines 21-40), wherein the carcinoma is a keratinizing squamous cell carcinoma (claim 2). It is administered daily in a dose of 2 mg to 20 mg, 5 mg to 20 mg, 10 mg to 16 mg, 10 mg to 14 mg, 8 mg, 10 mg, 12 mg, 14 mg, or 16 mg. 12 (claim 10). Claim 12 recites the compound of formula I is administered by an interval administration regimen with a daily 14-day administration period and followed by a 7-day rest period. Claim 13 states the compound can be administered with another antitumor drug simultaneously or sequentially. Claim 14 further defines the another antitumor drug and which may be a monoclonal antibody (see also claims 15-17). Claim 19 species the antibody may be durvalumab (defined in the specification as an anti-PD-L1 antibody at col. 9, lines 41-43).
The claims of ‘862 differ from the instant claims in that they do not recite the same antibody or any dosages thereof and treatment is not of STS.
WO 2020/239085 (Yang) teaches treatment of melanoma with the anti-PD-L1 antibody hu13V5-hIgG1 and -hIgG4 and 5G11-hIgG1 having the sequences of HCDR1-3 of SEQ ID NO:1-3 and 4-6 and LCDR1-3 of SEQ ID NO:7-9 and 10-12, respectively, and variable heavy and light chain regions of SEQ ID NO:13/15 and 14/16, respectively (p. 6, last full paragraph; [0010] of translation). The amount of antibody administered is 600-2400 mg and amount of anlotinib is 84-168 mg, with a treatment cycle that may be 21 days (claim 6). More specifically, a pharmaceutical composition comprising 6, 8, 10 or 12 mg anlotinib and 600-2400 mg anti-PD-L1 is taught in claim 4. The weight ratio of the anti-PD-L1 antibody and anlotinb is (0.35-29):1, (3.5-29):1, (3.5- 14.5):1 or (7-14.5):1 (claim 5). Administration of the antibody and anlotinib may be simultaneous or sequential (claim 9). In the example, patients were give 10 cycles, 21 days each, of 1200 mg anti-PD-L1 antibody hu5G11-hG1 by injection and 12 mg oral anlotinib (capsul form, section 1.2 of p. 11 through 1.5 of p. 12; [0160], [0171]-[0173] of translation). It is taught that anlotinib can be administered daily on days 1-14 of each 21-day cycle, while the antibody is administered only on the first day (p. 3, last third, [0043]-[0045] of translation). A pharmaceutical composition comprising the anti-PD-L1 antibody may have an antibody concentration of 10-60 mg/ml (p. 4, third paragraph; [0051] translation). A kit is claimed comprising a combination of anti-PD-L1 antibody and anlotinib (claims 5 and 12-18).
Zha teaches treatment of cancer by administration of an anti-human PD-L1 antibody (Example 1 and [0087]), including liposarcoma, antiosarcoma, endothelial sarcoma, leimyosarcoma, lymphangiosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, rhabdomyosarcoma, fibrosarcoma and myxosarcoma ([0089]). The antibody may be administered with an additional therapeutic agent and administration may be concurrent or sequential. They may be formulated separately or administered in the same formulation (([0095]). Anti-PD-L1 antibodies hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1are taught, including their sequences, heavy and light chain CDR1-3 of SEQ ID NO: 81-85 (5G11) and 93-98 (13C5) ([0109]), comprised by the humanized (hu) heavy and light chain variable regions (VH/VL) of SEQ ID NO:42/44 and 46/48, respectively (see also claim 5). Heavy chain of hu5G11-IgG1 and -IgG4 are SEQ ID NO:70 and 72, respectively, and light chain is SEQ ID NO:74. The heavy chain of hu13C5-IgG1 and -IgG4 are SEQ ID NO:76 and 78, respectively, and light chain is SEQ ID NO:80 ([0110]).
Shen et al. discusses the clinical use of anlotinib (1-((4-(4-fluoro-2-methyl-1h-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine, defined p. 2/11, col. 1, start of third paragraph), which is an oral receptor tyrosine kinase (RTK) inhibitor taken orally that targets multiple RTKs (Fig. 1 and p. 2/11, col. 1, third paragraph). Its antiangiogenic activity is stronger than 3 other such drugs, including sunitinib, sorafenib and ninetedanib (p. 2/11, start of col. 2). As discussed on p. 4/11, col. 1, second and third full paragraph, a phase I study showed that anlotinib caused tumor shrinkage in soft tissue sarcomas (STSs). This led to a single-arm phase II study in patients with advanced STS, including fibrous histocytoma, liposarcoma, leiomysarcoma, synovial sarcoma and others, who failed previous conventional treatment. For the phase II study, “Overall, anlotinib demonstrated better clinical benefits in many pathological types of STS.” A related phase IIb study in patients with advance STS who were treatment-intolerant or progressed on anthracycline-based chemotherapy showed overall response rate (ORR) and disease control rate (DCR) that was significantly higher than in the control group. “This trial further confirmed the efficacy and safety of anlotinib in advanced STS [44].” Based on clinical findings, the recommended dosing has been 12 mg daily for 2 weeks, followed by a 1-week break (p. 3/11, end of col. 1 and first paragraph of col. 2). There are ongoing clinical trials evaluating anlotinib in several STS subtypes, including leiomyosarcoma and synovial sarcoma (p. 7/11, col. 2, second full paragraph, also Table 3). It is concluded (p. 7/11, last paragraph), “Anlotinib has exceptional efficacy and acceptable toxicity for the treatment of advanced NSCLC [non-small cell lung cancer] and STS.”
It would have been obvious to treat STS with the method of ‘862, substituting anti-PD-L1 antibody hu5G11 or hu13C5 of Yang and Zha for durvalumab because both bind PD-L1 and were used to treat cancers. It would have been obvious to administer the anti-PD-L1 antibody in the dosage and in the regimen taught by Yang since that was for treatment of a cancer and the amounts of and timings of anlotinib were the same. It would have been obvious wherein the treatment was for STS, e.g., leimyosarcoma, in view of the prior art teachings thereof.
I) Claims 14-23 and 32-41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 12,390,458 (’458) in view of WO 2020/239085 A1 (Yang; cited in the IDS filed 02/09/2023, translation attached as an appendix to this Office action), WO 2016/022630 A1 (Zha, cited in the IDs filed 11/07/2024) and Shen et al. (J. Hematol. Oncol. 11:120, 11 pages, 2018).
The claims of the instant application are drawn to a method of treating a soft tissue sarcoma (STS) in a subject by administration of an antibody that binds PD-L1 and anlotinib. The anti-PD-L1 antibody has the 6 CDRs or the VH/VL of hu13C5 or hu5G11. The doses and administration schedule include 600-2400 mg anti-PD-L1 and 6, 8, 10 and/or 12 mg anlotinib, as well as a pharmaceutical composition comprising 600-2400 mg anti-PD-L1 antibody and 84-168 mg anlotinib. Anlotinib is administered on days 1-14 of each 3-week cycle and antibody is administered on day 1 of the cycle. Further claimed is a pharmaceutical composition having a concentration of 10-60 mg/mL anti-PD-L1 antibody.
The claims 1-3 of ‘458 are drawn to a therapeutic composition comprising an antibody which inhibits the interaction between PD-1 and PD-L1 and a tyrosine kinase inhibitor which is 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropylamine hydrochloride (defined in the specification as anlotinib in col. 5, lines 56-59). Claims 4-14 are drawn to a method of treating cancer which is non-small cell lung cancer. The treatment comprises administration of 84-168 mg/cycle of anlotinib, where the cycle is days 1-14 of treatment plus 1 week without (claims 11-12). The PD-1/PD-L1 inhibitor is an antibody PD-1 antibody is administered every 3 weeks.
The claims of ‘458 differ in that there is no PD-L1 antibody or dose thereof claimed.
WO 2020/239085 (Yang) teaches treatment of melanoma with the anti-PD-L1 antibody hu13V5-hIgG1 and -hIgG4 and 5G11-hIgG1 having the sequences of HCDR1-3 of SEQ ID NO:1-3 and 4-6 and LCDR1-3 of SEQ ID NO:7-9 and 10-12, respectively, and variable heavy and light chain regions of SEQ ID NO:13/15 and 14/16, respectively (p. 6, last full paragraph; [0010] of translation). The amount of antibody administered is 600-2400 mg and amount of anlotinib is 84-168 mg, with a treatment cycle that may be 21 days (claim 6). More specifically, a pharmaceutical composition comprising 6, 8, 10 or 12 mg anlotinib and 600-2400 mg anti-PD-L1 is taught in claim 4. The weight ratio of the anti-PD-L1 antibody and anlotinb is (0.35-29):1, (3.5-29):1, (3.5- 14.5):1 or (7-14.5):1 (claim 5). Administration of the antibody and anlotinib may be simultaneous or sequential (claim 9). In the example, patients were give 10 cycles, 21 days each, of 1200 mg anti-PD-L1 antibody hu5G11-hG1 by injection and 12 mg oral anlotinib (capsule form, section 1.2 of p. 11 through 1.5 of p. 12; [0160], [0171]-[0173] of translation). It is taught that anlotinib can be administered daily on days 1-14 of each 21-day cycle, while the antibody is administered only on the first day (p. 3, last third, [0043]-[0045] of translation). A pharmaceutical composition comprising the anti-PD-L1 antibody may have an antibody concentration of 10-60 mg/ml (p. 4, third paragraph; [0051] translation). A kit is claimed comprising a combination of anti-PD-L1 antibody and anlotinib (claims 5 and 12-18).
Zha teaches treatment of cancer by administration of an anti-human PD-L1 antibody (Example 1 and [0087]), including liposarcoma, antiosarcoma, endothelial sarcoma, leimyosarcoma, lymphangiosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, rhabdomyosarcoma, fibrosarcoma and myxosarcoma ([0089]). The antibody may be administered with an additional therapeutic agent and administration may be concurrent or sequential. They may be formulated separately or administered in the same formulation (([0095]). Anti-PD-L1 antibodies hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1are taught, including their sequences, heavy and light chain CDR1-3 of SEQ ID NO: 81-85 (5G11) and 93-98 (13C5) ([0109]), comprised by the humanized (hu) heavy and light chain variable regions (VH/VL) of SEQ ID NO:42/44 and 46/48, respectively (see also claim 5). Heavy chain of hu5G11-IgG1 and -IgG4 are SEQ ID NO:70 and 72, respectively, and light chain is SEQ ID NO:74. The heavy chain of hu13C5-IgG1 and -IgG4 are SEQ ID NO:76 and 78, respectively, and light chain is SEQ ID NO:80 ([0110]).
Shen et al. discusses the clinical use of anlotinib, which is an oral receptor tyrosine kinase (RTK) inhibitor taken orally that targets multiple RTKs (Fig. 1 and p. 2/11, col. 1, third paragraph). Its antiangiogenic activity is stronger than 3 other such drugs, including sunitinib, sorafenib and ninetedanib (p. 2/11, start of col. 2). As discussed on p. 4/11, col. 1, second and third full paragraph, a phase I study showed that anlotinib caused tumor shrinkage in soft tissue sarcomas (STSs). This led to a single-arm phase II study in patients with advanced STS, including fibrous histocytoma, liposarcoma, leiomysarcoma, synovial sarcoma and others, who failed previous conventional treatment. For the phase II study, “Overall, anlotinib demonstrated better clinical benefits in many pathological types of STS.” A related phase IIb study in patients with advance STS who were treatment-intolerant or progressed on anthracycline-based chemotherapy showed overall response rate (ORR) and disease control rate (DCR) that was significantly higher than in the control group. “This trial further confirmed the efficacy and safety of anlotinib in advanced STS [44].” Based on clinical findings, the recommended dosing has been 12 mg daily for 2 weeks, followed by a 1-week break (p. 3/11, end of col. 1 and first paragraph of col. 2). There are ongoing clinical trials evaluating anlotinib in several STS subtypes, including leiomyosarcoma and synovial sarcoma (p. 7/11, col. 2, second full paragraph, also Table 3). It is concluded (p. 7/11, last paragraph), “Anlotinib has exceptional efficacy and acceptable toxicity for the treatment of advanced NSCLC [non-small cell lung cancer] and STS.”
It would have been obvious to treat STS with the method of ‘458 in view of the prior art teaching of Zha and Shen that the anti-PD-L1 antibody and anlotinib were useful for treatment of STSs, e.g., leimyosarcoma. It would have been obvious to use as the inhibitor of the interaction between PD-1 and PD-L1 the hu5G11 or hu13C5 anti-PD-L1 antibody of the prior art for its known and expected properties and with a reasonable expectation of success. It would have been obvious to use it in the dosage and in the regimen taught by Yang since that was for treatment of a cancer and the amounts of and timings of anlotinib were the same.
J) Claims 14-23 and 32-41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 12,421,313 (‘313) in view of WO 2016/022630 A1 (Zha, cited in the IDs filed 11/07/2024) and Shen et al., (J. Hematol. Oncol. 11:120, 11 pages, 2018).
The claims of the instant and patent are both drawn to a method of treating a cancer in a subject by administration of an antibody that binds PD-L1 and anlotinib (instant claim 1 and claim 8 of ‘313). Both applications recite in the claims the same anti-PD-L1 antibody, having the 6 CDR, VH/VL or heavy and light chain of hu13C5 or hu5G11. They recite the same doses and administration schedule, including 1200 mg anti-PD-L1 and 6, 8, 10 and/or 12 mg anlotinib. Administration is claimed as anlotinib administered on days 1-14 of each 3-week cycle (84-168 mg total) and antibody is administered on day 1 of the cycle. A pharmaceutical combination comprises the anti-PD-L1 antibody and anlotinib in a weight ratio of (0.35—29):1 is recited in the claims of both.
The patent differs in that the treatment is of a tumor in the biliary system, liver cancer, triple negative breast cancer and/or lung cancer, with the instant claims drawn to treatment of soft tissue sarcoma (STS).
Zha teaches treatment of cancer by administration of an anti-human PD-L1 antibody (Example 1 and [0087]), including liposarcoma, angiosarcoma, endothelial sarcoma, leimyosarcoma, lymphangiosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, rhabdomyosarcoma, fibrosarcoma and myxosarcoma ([0089]). The antibody may be administered with an additional therapeutic agent and administration may be concurrent or sequential. They may be formulated separately or administered in the same formulation (([0095]). Anti-PD-L1 antibodies hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1are taught, including their sequences, heavy and light chain CDR1-3 of SEQ ID NO: 81-85 (5G11) and 93-98 (13C5) ([0109]), comprised by the humanized (hu) heavy and light chain variable regions (VH/VL) of SEQ ID NO:42/44 and 46/48, respectively (see also claim 5). Heavy chain of hu5G11-IgG1 and -IgG4 are SEQ ID NO:70 and 72, respectively, and light chain is SEQ ID NO:74. The heavy chain of hu13C5-IgG1 and -IgG4 are SEQ ID NO:76 and 78, respectively, and light chain is SEQ ID NO:80 ([0110]). The antibodies block binding of PD-L1 to PD-1 ([0116]). They also induced secretion of IFN-γ and IL-2 in mixed lymphocyte cultures and also reduced the inhibitory effect of T regulatory cells on secretion of IFN-γ by T effector cells ([0118]-[0119]). They enhanced IFN-γ secretion by T cells ([0120]).
Shen et al. discusses the clinical use of anlotinib, which is an oral receptor tyrosine kinase (RTK) inhibitor taken orally that targets multiple RTKs (Fig. 1 and p. 2/11, col. 1, third paragraph). Its antiangiogenic activity is stronger than 3 other such drugs, including sunitinib, sorafenib and ninetedanib (p. 2/11, start of col. 2). As discussed on p. 4/11, col. 1, second and third full paragraph, a phase I study showed that anlotinib caused tumor shrinkage in soft tissue sarcomas (STSs). This led to a single-arm phase II study in patients with advanced STS, including fibrous histocytoma, liposarcoma, leiomysarcoma, synovial sarcoma and others, who failed previous conventional treatment. For the phase II study, “Overall, anlotinib demonstrated better clinical benefits in many pathological types of STS.” A related phase IIb study in patients with advance STS who were treatment-intolerant or progressed on anthracycline-based chemotherapy showed overall response rate (ORR) and disease control rate (DCR) that was significantly higher than in the control group. “This trial further confirmed the efficacy and safety of anlotinib in advanced STS [44].” Based on clinical findings, the recommended dosing has been 12 mg daily for 2 weeks, followed by a 1-week break (p. 3/11, end of col. 1 and first paragraph of col. 2). There are ongoing clinical trials evaluating anlotinib in several STS subtypes, including leiomyosarcoma and synovial sarcoma (p. 7/11, col. 2, second full paragraph, also Table 3). It is concluded (p. 7/11, last paragraph), “Anlotinib has exceptional efficacy and acceptable toxicity for the treatment of advanced NSCLC [non-small cell lung cancer] and STS.”
It would have been obvious to treat STS with the method of ‘313 in view of the prior art teaching of the applicability of the anti-PD-L1 antibody and anlotinib in the treatment of STS.
K) Claims 14-23 and 32-41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 12,472,173 (‘173) view of WO 2020/239085 A1 (Yang; cited in the IDS filed 02/09/2023, translation attached as an appendix to this Office action) and as evidenced by Shen et al., (J. Hematol. Oncol. 11:120, 11 pages, 2018).
The claims of the instant application are drawn to a method of treating a soft tissue sarcoma (STS) in a subject by administration of an antibody that binds PD-L1 and anlotinib. The anti-PD-L1 antibody has the 6 CDRs or least the VH/VL of hu13C5 or hu5G11. The doses and administration schedule include 600-2400 mg anti-PD-L1 and 6, 8, 10 and/or 12 mg anlotinib, as well as a pharmaceutical composition comprising 600-2400 mg anti-PD-L1 antibody and 84-168 mg anlotinib. Anlotinib is administered on days 1-14 of each 3-week cycle and antibody is administered on day 1 of the cycle. Further claimed is a pharmaceutical composition having a concentration of 10-60 mg/mL anti-PD-L1 antibody.
Patent ‘173 claims a method of treating a soft tissue sarcoma comprising administering the compound of formula 1, 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropylamine, and toripalimab (claim 1). Treatment according to claim 2 is after STS has progressed or recurred after chemotherapy treatment or has not previously been systemically treated with a tyrosine kinase inhibitor (TKI) or PD-1/PD-L1 inhibitor (claim 3). The compound of formula 1 is administered at a dose of 6, 8, 10 or 12 mg once daily and toripalimab is administered once every week, every 2, 3 or 4 weeks in a single dose up to 600 mg (claims 5-6). Toripalimab is defined in the specification as an anti-PD-1 antibody (col. 8, lines 23-24). The compound of formula 1 is defined as anlotinib (col. 1, lines 63-67)
The claims of ‘173 differ from the instant claims in that they do not recite the same antibody or any dosages thereof.
WO 2020/239085 (Yang) teaches treatment of melanoma with the anti-PD-L1 antibody hu13V5-hIgG1 and -hIgG4 and 5G11-hIgG1 having the sequences of HCDR1-3 of SEQ ID NO:1-3 and 4-6 and LCDR1-3 of SEQ ID NO:7-9 and 10-12, respectively, and variable heavy and light chain regions of SEQ ID NO:13/15 and 14/16, respectively (p. 6, last full paragraph; [0010] of translation). The amount of antibody administered is 600-2400 mg and amount of anlotinib is 84-168 mg, with a treatment cycle that may be 21 days (claim 6). More specifically, a pharmaceutical composition comprising 6, 8, 10 or 12 mg anlotinib and 600-2400 mg anti-PD-L1 is taught in claim 4. The weight ratio of the anti-PD-L1 antibody and anlotinb is (0.35-29):1, (3.5-29):1, (3.5- 14.5):1 or (7-14.5):1 (claim 5). Administration of the antibody and anlotinib may be simultaneous or sequential (claim 9). In the example, patients were give 10 cycles, 21 days each, of 1200 mg anti-PD-L1 antibody hu5G11-hG1 by injection and 12 mg oral anlotinib (capsul form, section 1.2 of p. 11 through 1.5 of p. 12; [0160], [0171]-[0173] of translation). It is taught that anlotinib can be administered daily on days 1-14 of each 21-day cycle, while the antibody is administered only on the first day (p. 3, last third, [0043]-[0045] of translation). A pharmaceutical composition comprising the anti-PD-L1 antibody may have an antibody concentration of 10-60 mg/ml (p. 4, third paragraph; [0051] translation). A kit is claimed comprising a combination of anti-PD-L1 antibody and anlotinib (claims 5 and 12-18).
Shen et al. defines 1-((4-(4-fluoro-2-methyl-1h-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine as anlotinib (p. 2/11, col. 1, start of third paragraph)
It would have been obvious to treat STS with the method of ‘173, substituting anti-PD-L1 antibody hu5G11 or hu13C5 of Yang and Zha for toripalimab because both inhibited the binding of PD-1 to PD-L1 and were used to treat cancers. It would have been obvious to administer the anti-PD-L1 antibody in the dosage and in the regimen taught by Yang since that was for treatment of a cancer and the amounts of and timings of anlotinib were the same.
Prior Art
The prior art made of record and not relied upon is considered pertinent to Applicant's disclosure.
US Patent 10,544,125 B2 teaches anlotinib as Compound I or AL3818 (1-((4-(4-fluoro-2-methyl-1h-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine, Abstract). Use of the compound includes in the treatment of sarcoma, including in combination with a PD-L1 immunotherapy, such as an antibody (e.g., Example 15). However, the amounts of the compound do not appear to be in the range of the instant claims (e.g., Example 11) and no particular anti-PD-L1 antibody or dosage thereof is taught.
US Patents 9,968,597 (published May 18, 2018 and the national stage filing of PCT publication WO 2015/185014 A1 that is cited in the IDS filed 11/07/2024) and US 10,183,017 B2 (published Jan. 22, 2019) have the same applicant as the instant application and teach a method of treating STSs by administration of Compound I (1-((4-(4-fluoro-2-methyl-1h-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropan-amine, col. 3, lines 29-65) in a 21-day cycle with treatment for the first 14 days plus a week off and in a dosage of 2-20 mg, but specifically a capsule comprising 12 mg/day (col. 3, lines 29-65, col. 12, lines 10-16, and, e.g., col. 7, lines 10-13). The table in col. 10, Example 2, lists the contents of the capsules, including 12mg of Compound I (see also Example 4). Table 1 shows therapeutic effect for STS patients treated as above (Examples 5-8). These patents are cumulative with Shen et al. relied upon above.
Chi et al. (J. Clin. Oncol. 36(15)Suppl:11503, 2018) teaches results of a randomized, double-blind, placebo-controlled and multi-centered clinical trial using anlotinib (12 mg per day for 2 weeks on and 1 week off) to treat metastasis soft tissue sarcoma (Methods). It was shown to greatly increase progression-free survival (PFS) and disease control rate (Results). The Conclusions are, “Anlotinib is a new treatment option for patients with advanced STS after failure of standard chemotherapy.” These are results from clinicaltrial.gov study NCT02449343. This reference is cumulative with Shen et al. (2018, supra) for showing the clinical success of anlotinib for treatment of STSs and the recommended dosage regimen.
Conclusion
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Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
December 12, 2025