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 .
DETAILED ACTION
Claims 1-20 are pending in the instant application and being examined on the merits.
Priority
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C.
119(a)-(d) prior to declaration of an interference, a certified English translation of the
foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and
41.202(e).
Failure to provide a certified translation may result in no benefit being accorded
for the non-English application. The effective priority date is the filing date of
PCT/JP2022/019622 filed on 5/9/2022 in the absence of a certified translation of
JP2021-079655 filed on 5/10/2021.
Claim Interpretation
Regarding instant claim 1, the modified antibody is interpreted as comprising a non-charged hydrophilic polymer block, wherein the non-charged hydrophilic polymer block, an environment-responsive bond and the antibody are linked in this order, each of the linkages is optionally via a spacer, and the environment-responsive bond is cleaved under a reducing environment.
Regarding instant claim 7, the specification defines the term “lower alkylene” as a number of carbon atoms of 1-8 (specification, page 28, second paragraph).
Regarding instant claim 7, the specification defines the term “stable” as stable enough to exist in the blood with stability over a time required for delivery to a target
tissue (for example, the brain parenchyma or a tumor tissue) with the blood flow after administration (specification, page 55, second paragraph).
Regarding instant claim 12, the specification defines the term "targeting molecule'' as a molecule moiety which may be linked to an antibody moiety and is different from the antibody moiety (pages 22-23 bridging sentence).
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 12-18 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding instant claim 12, the term “exposes” renders the metes and bounds of the claim unclear. It is unclear in the claim as to whether the antibody is required to perform a function that “exposes” the targeting molecule or rather the antibody further includes an exposed targeting molecule. Claims 13-15 are dependent on claim 12 without further clarifying whether a function is required and are also rejected.
To promote compact prosecution, in instant claim 12 “exposes a” will be considered as both “exposes a” and “further includes an exposed”.
Claim 16 recites the limitation " the antibody that binds to an immune checkpoint molecule to inhibit an immune checkpoint " in line 2-3. There is insufficient antecedent basis for this limitation in the claim. The antibody in instant claim 1 has not introduced that it binds to an immune checkpoint molecule to inhibit an immune checkpoint. Claims 17-18 are dependent on claim 16 and further include the antecedent basis issue and are also rejected
To promote compact prosecution, in instant claim 16 “the antibody that binds to an immune checkpoint molecule to inhibit an immune checkpoint” will be exchanged with “the modified antibody”.
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 2-3, 6, and 12-15 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.
Instant claims 2-3 and 6 claim a change in binding affinity of an antigen of interest but the claim does not require the antigen of interest is bound by the modified antibody;
Instant claims 2-3 claim a change in binding affinity of an antigen of interest of less than 5 or 10%, but the binding affinity changes are claimed functionally without a structure and the Applicant does not have possession of a structure activity relationship for all modes of decreased binding affinity of an antibody comprising the claimed modified antibody;
Instant claim 12 claims the antibody exposes a targeting molecule, but the instant specification does not show an antibody is required to perform a function that “exposes” the targeting molecule. Instant claims 13-15 are dependent on claim 12 without further narrowing the subject matter to requiring the antibody to perform a function to expose the targeting molecule.
Scope of the claimed genus
Instant claims 2-3 and 6 claim “an antigen of interest” without requiring binding to a modified antibody that is modified with a non-charged hydrophilic polymer block, wherein the non-charged hydrophilic polymer block, an environment-responsive bond and the antibody are linked in this order, each of the linkages is optionally via a spacer, and the environment-responsive bond is cleaved under a reducing environment;
Instant claims 2-3 and 6 claim a modified antibody that is modified with a non-charged hydrophilic polymer block, wherein the non-charged hydrophilic polymer block, an environment-responsive bond and the antibody are linked in this order, each of the linkages is optionally via a spacer, and the environment-responsive bond is cleaved under a reducing environment, wherein a binding affinity for an antigen of interest is 5% or 10% of the binding affinity before modification, wherein the binding affinity is claimed functionally without a structure or a structure activity relationship for decreased binding affinity of an antibody comprising the claimed modified antibody.
Instant claims 12-15 claim a modified antibody that is modified with a non-charged hydrophilic polymer block, wherein the non-charged hydrophilic polymer block, an environment-responsive bond and the antibody are linked in this order, each of the linkages is optionally via a spacer, and the environment-responsive bond is cleaved under a reducing environment, wherein the antibody exposes a targeting molecule.
Summary of Species disclosed in the original specification
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
1)-3) The instant disclosure teaches:
a) an unmodified anti-PD-L1 antibody and a glucose-PEG-S-S-anti-PD-L1 antibody that blocks PD-L1 binding to the modified antibody in the absence of a reducing environment (Fig. 3-7 and 21);
b) glucose-PEG-S-S-anti-PD-L1 antibodies with different levels of glucose conjugation have different plasma, tumor, and endothelial wall concentrations and anti-tumor efficacy (Fig. 8-11);
c) Gluc25-PEG-S-S-aPD-L1 was elevated in brains, caused more activation of CD* T cells, increased blood IFN-gamma, suppressed Treg (Foxp3+ T cells), increased effector memory T-cells (CD44hi CD62Llow) and decreased tumor recurrence when compared to an unmodified anti-PD-L1 and a Gluc0-PEG-S-S-aPD-L1 antibody (Fig 13-17);
d) an unmodified anti-CTLA4 antibody and a glucose-S- anti-PD-L1 antibody (Fig. 3 and 21); and
e) a GSH sensitive, PEG blocking modified T-DM1 antibody was produced in Fig. 22-23.
Thus, the modified antibody is required to bind the modified antibody antigen target. Additionally, while modification of three antibodies has been demonstrated in the instant disclosure to conditionally block the antigen binding site with a PEG polymer, the instant disclosure does not show a structure activity relationship for all possible modes of decreasing binding affinity of a modified antibody for values below 5% or 10% of the antibody prior to modification that would enable a person having ordinary skill in the art to select the all antibody modifications necessary to functionally decrease the binding affinity 5% or 10% or less.
State of the Relevant Art
At the time of the filing of the instant application, it was well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three “complementarity determining regions” (“CDRs”) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro & Fransson, Frontiers in Bioscience 2008; 13:1619-33; (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7). Chiu ML et al. (Antibodies 2019 8, 55, 1-80) taught the antigen binding of antibodies often results in conformational changes in the contact surface areas of both the antibody and the antigen (page 5, first paragraph). Thus, an antigen of interest would be required to bind the modified antibody.
The prior art has taught non-charged hydrophilic polymers can sterically block modified antibodies. WO 2020/186090 (Whitney MA et al.) taught a composition of a modified cetuximab antibody that is modified on lysine residues with a linker comprising a protease cleavage site, and a non-charged hydrophilic polymer block of polyethylene glycol (PEG), wherein the PEG modification effectively blocks antibody target binding more than 99% such that a 1/50 dilution of the modified antibody binds the antibody target at an equal amount to 1/20,000 dilution of an unmodified cetuximab antibody binds the target ([1/20,000] / [1/50] =0.0025 ), and wherein the PEG blocking domain is removed via protease activation and release of the non-charged hydrophilic polymer block PEG (Example 4, page 77, last two paragraphs and Figs 6-8). ‘090 further taught modification of other antibodies including the immune checkpoint PD-L1 antibody pembrolizumab to reduce side effects, wherein pembrolizumab can cause serious side effects throughout the body including colitis and perforations in the intestines, hepatitis of the liver, skin rash, and nerve damage (page 69, first paragraph and section title). Thus, while modification of antibodies has been demonstrated in the prior art to conditionally block the antigen binding site with a PEG polymer, the prior art does not show a structure activity relationship for all possible modes of decreasing binding affinity of a modified antibody for values below 5% or 10% of the antibody prior to modification that would enable a person having ordinary skill in the art to select the antibody modifications necessary to decrease the binding affinity 5% or 10% or less.
US 2016/0287714 (Kataoka K et al.) taught a method for delivering a drug to a brain tissue, comprising administering a conjugate of the drug and a GLUT1 targeting ligand or a conjugate comprising the drug and a GLUT1 targeting molecule ligand linked via a linker to a subject (pages 25-26, [142]). ‘714 taught an antibody conjugated to a moiety comprising PEG-glucose as the targeting molecule, wherein the modified antibody conjugated with PEG-glucose showed higher levels of antibody in the brain parenchyma compared to control (pages 34-35, [211], [216] and Fig. 10). The antibody further includes an exposed targeting molecule of PEG-glucose as the targeting molecule, but the antibody does not perform a function that “exposes” the targeting molecule.
Claim Rejections – 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 5, 16, and 18-20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 2019/0055321 ( Krystek SR et al.) and evidenced by Baldwin AD et al. (Bioconjug Chem. 2011 Sep 26;22(10):1946–1953).
Regarding instant claims 1, 5, 16, and 18-20, ‘321 taught a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a modified CTLA4 antibody conjugate with a non-charged hydrophilic polymer block, wherein the modified CTLA4 antibody conjugate comprised in order: a) a non-charged hydrophilic polymer block of PEG; b) a spacer linker; c) an environment-responsive bond of a maleimide to a cysteine that is cleaved under a reducing condition; and d) a modified CTLA4 antibody (Fig. 7 and 11A-B). Regarding the environment-responsive bond of a maleimide to a cysteine that is cleaved under a reducing condition, Baldwin evidenced the rate of thiol exchange of maleimide-thiol adducts vary with the concentration of reductant (page 1951, left column and Fig. 4). Thus, a maleimide bound to a cysteine is an environmental-responsive bond that is cleaved under a reducing condition and the pharmaceutical composition above meets the claim limitations of instant claims 1, 5, 16, and 18-20.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-3, 5-6, 9-17, and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/186090 (Whitney MA et al.), Hao C et al. (Front Oncol. 2020 Jun 24;10:1015), US 2016/0287714 (Kataoka K et al.), and US 2018/0185281 ( Kataoka K et al. IDS reference).
Regarding instant claims 1-3 and 5-6, ‘090 taught a composition of a modified cetuximab antibody that is modified on lysine residues with a linker comprising a protease cleavage site, and a non-charged hydrophilic polymer block of polyethylene glycol (PEG), wherein the 5K PEG modification effectively blocks antibody target binding more than 99% such that a 1/50 dilution of the modified antibody binds the antibody target at an equal amount to 1/20,000 dilution of an unmodified cetuximab antibody binds the target ([1/20,000] / [1/50] =0.0025 ), and wherein the PEG blocking domain is removed via protease activation and release of the non-charged hydrophilic polymer block PEG (Example 4, page 77, last two paragraphs and Figs 6-8). Regarding instant claims 9-11 and 16-17, ‘090 taught modification of other antibodies including the immune checkpoint PD-L1 antibody pembrolizumab to reduce side effects, wherein pembrolizumab can cause serious side effects throughout the body including colitis and perforations in the intestines, hepatitis of the liver, skin rash, and nerve damage (page 69, first paragraph and section title). Regarding instant claim 19, ‘090 taught antibody drugs that can have serious off target affects and limit use are antibody drug conjugates (ADCs), wherein the nature of a toxic drug, conjugated to a targeting antibody has an increased potential for negative side effects compared to antibody alone (page 69, last paragraph). ‘090 taught to address these antibody related side effects, the present invention provides a platform technology that can be modified to modulate an antibody of interest (page 69, last paragraph). Regarding instant claim 20, ‘090 taught the composition as a pharmaceutical composition (page 63, last paragraph). ‘090 taught conjugation to a lysine and prior to conjugation with the first linker site is a reactive functional group of p-nitrophenyl (page 41, second paragraph).
‘090 did not teach: 1) an environment-responsive bond cleaved under a reducing environment; or 2) a glucose GLUT1 targeting ligand on the modified antibody of glucose, but this is obvious in view of Hao, ‘714, and ‘281.
Regarding instant claims 1, 9-11 and 16-17, Hao taught high expression of PD-L1 in glioblastoma tumor tissues is associated with poor survival of patients, and PD-L1 may act as a prognostic predictor and an effective therapeutic target for glioblastoma (abstract). Hao taught preclinical data in murine models of glioma have provided support for PD-L1 checkpoint inhibitors implementation in GBM patients (page 7, right column, second paragraph).
Regarding instant claims 1 and 12-15, ‘714 taught a method for delivering a drug to a brain tissue, comprising administering a conjugate of the drug and a GLUT1 ligand or a conjugate comprising the drug and a GLUT1 ligand linked via a linker to a subject (pages 25-26, [142]). ‘714 taught an antibody conjugated to a moiety comprising PEG-glucose, wherein the modified antibody conjugated with PEG-glucose showed higher levels of antibody in the brain parenchyma compared to control (pages 34-35, [211], [216] and Fig. 10).
Regarding instant claims 1-3 and 5-6, ‘281 taught a carrier comprising a glucose-PEG-S-S moiety is cleaved in a reductive environment (Fig. 2), wherein the presence of the disulfide bond leads to cleavage under a reductive environment, and wherein glutathione concentrations in the brain parenchyma are 1-3 mM compared to about 0.01 mM in blood (Fig. 4).
Regarding instant claims 1-3, 5-6, 9-17, and 19-20, it would have been obvious for a person having ordinary skill in the art to modify the effective composition of ‘090 of a modified cetuximab antibody that is modified on lysine residues with a linker comprising a protease cleavage site, and a non-charged hydrophilic polymer block of polyethylene glycol (PEG), wherein the 5K PEG modification effectively blocks antibody target binding more than 99% such that a 1/50 dilution of the modified antibody binds the antibody target at an equal amount to 1/20,000 dilution of an unmodified cetuximab antibody binds the target ([1/20,000] / [1/50] =0.0025 ), and wherein the PEG blocking domain is removed via protease activation and release of the non-charged hydrophilic polymer block PEG: - by:
Exchanging cetuximab for the immune checkpoint PD-L1 antibody pembrolizumab in view of ‘090;
Use the composition to target cancers of the brain and in a pharmaceutical composition in view of Hao and ‘090;
Include a glucose at the front of the PEG moiety to target the antibody to the brain in view of ‘714;
Exchanging the protease sensitive site within the linker to an environment-responsive bond cleaved under a reducing environment comprising a S-S linker in view of ‘281.
Include a drug conjugate on the anti-PD-L1 antibody in view of ‘090;
This is obvious because:
1)‘090 taught modification of other antibodies including the immune checkpoint PD-L1 antibody pembrolizumab to reduce side effects, wherein pembrolizumab can cause serious side effects throughout the body including colitis and perforations in the intestines, hepatitis of the liver, skin rash, and nerve damage (page 69, first paragraph and section title).
2a) Hao taught: i) high expression of PD-L1 in glioblastoma tumor tissues is associated with poor survival of patients, and PD-L1 may act as a prognostic predictor and an effective therapeutic target for glioblastoma; and 2) preclinical data in murine models of glioma have provided support for PD-L1 checkpoint inhibitors implementation in GBM patients;
2b) ‘090 taught the composition as a pharmaceutical composition;
3) ‘714 taught: i) a method for delivering a drug to a brain tissue, comprising administering a conjugate of the drug and a GLUT1 ligand or a conjugate comprising the drug and a GLUT1 ligand linked via a linker to a subject; ii) an antibody conjugated to a moiety comprising PEG-glucose, wherein the modified antibody conjugated with PEG-glucose showed higher levels of antibody in the brain parenchyma compared to control;
4) ‘281 taught a carrier comprising an environment-responsive bond cleaved under a reducing environment comprising glucose-PEG-S-S, wherein the presence of the disulfide bond leads to cleavage under a reductive environment, and wherein glutathione concentrations in the brain parenchyma are 1-3 mM compared to about 0.01 mM in blood;.
5) ‘090 taught: i) antibody drugs that can have serious off target affects and limit use are antibody drug conjugates (ADCs), wherein the nature of a toxic drug, conjugated to a targeting antibody has an increased potential for negative side effects compared to antibody alone; ii) to address these antibody related side effects, the present invention provides a platform technology that can be modified to modulate an antibody of interest.
There is a reasonable expectation of success because:
1) ‘090 taught modification of other antibodies including the immune checkpoint PD-L1 antibody pembrolizumab to reduce side effects, wherein pembrolizumab can cause serious side effects throughout the body including colitis and perforations in the intestines, hepatitis of the liver, skin rash, and nerve damage and the PEG would also block other antibodies.
2a) Hao taught: i) high expression of PD-L1 in glioblastoma tumor tissues is associated with poor survival of patients, and PD-L1 may act as a prognostic predictor and an effective therapeutic target for glioblastoma; and ii) preclinical data in murine models of glioma have provided support for PD-L1 checkpoint inhibitors implementation in GBM patients;
2b) a pharmaceutical composition would be necessary for cancer treatment;
3) ‘714 taught an antibody conjugated to a moiety comprising PEG-glucose, wherein the modified antibody conjugated with PEG-glucose showed higher levels of antibody in the brain parenchyma compared to control;
4) ‘281 taught a carrier comprising an environment-responsive bond cleaved under a reducing environment comprising glucose-PEG-S-S moiety, wherein the presence of the disulfide bond leads to cleavage under a reductive environment, and wherein glutathione concentrations in the brain parenchyma are 1-3 mM compared to about 0.01 mM in blood.
5) ‘090 taught: i) antibody drugs that can have serious off target affects and limit use are antibody drug conjugates (ADCs), wherein the nature of a toxic drug, conjugated to a targeting antibody has an increased potential for negative side effects compared to antibody alone (page 69, last paragraph); and ii) to address these antibody related side effects, the present invention provides a platform technology that can be modified to modulate an antibody of interest.
This would produce a pharmaceutical composition (instant claim 20) for brain cancer of a modified immune checkpoint PD-L1 antibody pembrolizumab (instant claim 9-11) which is expressed on cancer cells and neutralizes interaction between immune checkpoint molecules on immune cells (instant claims 16-17 ) and is a cancer antigen (instant claim 11) or ADC (instant claim 19) that is modified on lysine residues with a linker comprising, in order: i) an environment-responsive bond cleaved under a reducing environment comprising S-S; ii) a 5K non-charged hydrophilic polymer block of polyethylene glycol (PEG); iii) a glucose which is a GLUT1 ligand and is exposed on the outside of the linker (instant claim 12-15), wherein the PEG modification effectively blocks antibody target binding more than 99%, and wherein the PEG blocking domain is removed in an increased reducing environment (instant claim 1), wherein the modification would naturally have a binding affinity for an antigen of interest of 5% or less of the antibody before modification (instant claims 2-3), wherein the environment-responsive bond is naturally cleaved under a reducing environment in a brain parenchyma or under a reducing environment in a tumor tissue (instant claim 5), wherein when the environment-responsive bond is cleaved, the binding affinity for an antigen of interest is naturally recovered (instant claim 6).
Claims 1-3, 5-6, and 9-20 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/186090 (Whitney MA et al.), Hao C et al. (Front Oncol. 2020 Jun 24;10:1015. doi: 10.3389/fonc.2020.01015), US 2016/0287714 ( Kataoka K et al.), and US 2018/0185281 ( Kataoka K et al. IDS reference) as applied to claims 1-3, 5-6, 9-17, and 19-20 above, and further in view of Zheng J et al. (Int J Radiat Oncol Biol Phys 2013 86(2):343-9).
‘090, Hao, ‘714, and ‘281 are described above.
‘090 did not teach PEG modification of an anti-PD-1 antibody but this is obvious in view of Zheng.
Regarding instant claim 18, Zheng taught a treatment comprising an anti-PD-1 blockade results in increased survival in subjects with orthotopic brain tumors (abstract). Zheng taught these studies provide strong preclinical evidence to support combination trials in patients with GBM (abstract). Zheng taught PD-1 is a surface receptor expressed on activated and exhausted T cells, which mediate T cell inhibition upon binding with its ligand PD-L1, expressed on many tumor types including human GBMs (abstract).
Regarding instant claim 18, it would have been obvious for a person having ordinary skill in the art to modify the pharmaceutical composition of ‘090, Hao, ‘714, and ‘281 above comprising an immune checkpoint antibody PD-L1: by –
Exchanging the anti-PD-L1 antibody pembrolizumab for an anti-PD-1 antibody of Zheng, wherein the PD-1 is expressed on immune cells.
This is obvious with a reasonable expectation of success because: 1) Zheng taught: a) a treatment comprising an anti-PD-1 blockade results in increased survival in subjects with orthotopic brain tumors; b) these studies provide strong preclinical evidence to support combination trials in patients with GBM; and c) PD-1 is a surface receptor expressed on activated and exhausted T cells, which mediate T cell inhibition upon binding with its ligand PD-L1, expressed on many tumor types including human GBMs. Thus, the PEG moieties would still block the PD-1 antibody in the absence of a reducing environment, be targeted to the brain with glucose, cleave the blocking moiety in the brain reductive environment, and bypass the PD-L1 expressed on GBM cancers.
Claims 1-17 and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/186090 (Whitney MA et al.), Hao C et al. (Front Oncol. 2020 Jun 24;10:1015. doi: 10.3389/fonc.2020.01015), US 2016/0287714 ( Kataoka K et al.), and US 2018/0185281 (Kataoka K et al. IDS reference) as applied to claims 1-3, 5-6, 9-17, and 19-20 above, and further in view of CN106866978A (Cao A et al.) and evidenced by translated CN106866978A.
‘090, Hao, ‘714, and ‘281 are described above.
Regarding instant claims 4 and 7-8, ‘090 further taught conjugation to a lysine and prior to conjugation with the first linker site is a reactive functional group of p-nitrophenyl (page 41, second paragraph).
‘090 did not teach a linker comprising -C(O)-O-L1-S-S-L2-(a non-charged hydrophilic polymer block), but this is obvious in view of ‘978.
Regarding instant claims 4 and 7-8, ‘978 taught a PEG polymer block wherein a PEG-PCN-PEG polymer block was sensitive to reductive degradation via an environment with higher levels of reducing agent (Fig. 6), wherein the composition comprised the structure:
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and was effectively cleaved by higher levels of reducing agent (Figs. 5-7). ‘978 taught preparation of a PEG-PCN-PEG polymer, wherein the reaction comprised an amino-PEG conjugated to a p-nitrophenyl moiety that further comprised a S-S that was sensitive to a reductive environment and a p-nitrophenyl moiety
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(Fig. 1B).
Regarding instant claims 4 and 7-8, it would have been obvious for a person having ordinary skill in the art to modify the pharmaceutical composition of ‘090, Hao, ‘714, and ‘281 above: by –
Including the modified antibody as: a) an anti-PD-L1 antibody pembrolizumab modified on lysine residues; and a conjugate comprising b) a reducing environment sensitive linker, a PEG hydrophilic blocking polymer, and glucose of:
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in the modified antibody in view of ‘978, wherein the N at the beginning is from the antibody lysine residue.
This is obvious because:
1a) ‘090 further taught conjugation to a lysine and prior to conjugation with the first linker site is a reactive functional group of p-nitrophenyl
1b) ‘978 taught a non-charged hydrophilic polymer block PEG wherein a PEG-PCN-PEG polymer block was sensitive to reductive degradation via an environment with higher levels of reducing agent, wherein the composition comprised
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and was effectively cleaved by higher levels of reducing agent. Thus, a linker comprising the PEG-reducing environment linker was known to be effective;
1c) ‘978 taught preparation of a PEG-PCN-PEG polymer, wherein the reaction comprised a an amino-PEG conjugated to a p-nitrophenyl moiety that further comprised a S-S that was sensitive to a reductive environment and a p-nitrophenyl moiety.
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;
Thus, a person having ordinary skill in the art would obviously exchange the p-nitrophenyl conjugation to the amine containing CN linker above for an amine from lysines of the modified antibody of ‘090, Hao, ‘714, and ‘281 above. This would conjugate the modified antibody to the linker comprising DTDE-PNC above which contains an environment-responsive bond cleaved under a reducing environment, wherein the DTDE-PNC is further conjugated to an amine group for a non-charged hydrophilic polymer block of polyethylene glycol (PEG), which would further include a glucose for targeting GLUT1.
There is a reasonable expectation of success because:
1a) p-nitrophenyl groups are known to be used for conjugation to lysine residues and the amine of the lysine would be expected to also react as shown for the CN amine above;
1b) ‘978 taught a PEG polymer block wherein a PEG-PCN-PEG polymer block was sensitive to reductive degradation via an environment with higher levels of reducing agent, wherein the composition comprised
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and was effectively cleaved by higher levels of reducing agent. Thus, a linker comprising the PEG-reducing environment linker was known to be effective;
1c) ‘978 taught preparation of a PEG-PCN-PEG polymer, wherein the reaction comprised a an amino-PEG conjugated to a p-nitrophenyl moiety that further comprised a S-S that was sensitive to a reductive environment and a p-nitrophenyl moiety.
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;
Thus, a person having ordinary skill in the art would have a reasonable expectation of success to exchange the p-nitrophenyl conjugation to the amine containing CN linker above for an amine from lysines of the modified antibody of ‘090, Hao, ‘714, and ‘281 above. This would conjugate the modified antibody to the linker comprising DTDE-PNC above which contains an environment-responsive bond cleaved under a reducing environment, wherein the DTDE-PNC is further conjugated to an amine group for a non-charged hydrophilic polymer block of polyethylene glycol (PEG), which would further include a glucose for targeting GLUT1.
This would produce a pharmaceutical composition for brain cancer of a modified immune checkpoint PD-L1 antibody pembrolizumab which is expressed on cancer cells and neutralizes interaction between immune checkpoint molecules on immune cells and is a cancer antigen or ADC that is modified on lysine residues with a linker comprising, in order: a) an anti-PD-L1 antibody pembrolizumab modified on lysine residues; and a conjugate comprising b) a reducing environment sensitive linker, a 5K PEG hydrophilic blocking polymer, and glucose of:
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in the modified antibody, wherein the 5K PEG modification effectively blocks antibody target binding more than 99%, and wherein the PEG blocking domain is removed in an increased reducing environment, wherein the modification would naturally have a binding affinity for an antigen of interest of 5% or less of the antibody before modification, wherein the environment-responsive bond is naturally cleaved under a reducing environment in a brain parenchyma or under a reducing environment in a tumor tissue, wherein when the environment-responsive bond is cleaved, the binding affinity for an antigen of interest is naturally recovered, which naturally does not substantially or significantly bind to an antigen of interest under a serum environment (instant claim 4), and further meets the claim limitations of instant claims 7-8.
Conclusion
Claims 1-20 are rejected.
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/J.J.S./Examiner, Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643
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