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 .
Duty to Disclose
Applicants are kindly reminded of their duty to disclose pursuant to 37 C.F.R. 1.56 which encompasses the citation of references material to patentability of which Applicants are aware, such as references that may have been cited in the International Search Report of the parent applicant or in the specification.
Response to Amendment
The amendment filed 19 November 2025 is acknowledged. Claims 4, 6-8, 10-15, and 17-23 are canceled. New claims 24-34 are added.
Claim Status
Claims 1-3, 5, 9, 16, and 24-34 are pending and under examination in the instant office action.
Withdrawal of Rejections
The rejections of claims 4, 6-8, 10-15, and 17-23 are moot in view of the cancellation of the claims.
The rejection of claim 6 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is moot in view of the cancellation of claim 6.
The rejection of claims 1-23 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112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn in view of the amendment to the claims.
The rejection of claims 1-4, 7, and 16-23 under 35 U.S.C. 102(a)(1) as being anticipated by US 20070231333 A1 to Boghaert et. al. published 4 October 2007 is withdrawn in view of the amendment to the claims.
The rejection of claim 5 under 35 U.S.C. 103 as being unpatentable over US 20070231333 A1 to Boghaert et. al. published 4 October 2007 as applied to claims 1 and 4 above, and further in view of WO 2019027973 to Sandesh et. al. and US 20170210803 to Willingham et. al. is withdrawn in view of the amendment to the claims.
The provisional rejection of claims 1-5, 14, 16, and 23 are under 35 U.S.C. 101 as claiming the same invention as that of claim 1-5, 14, 16, and 20 of copending Application No. 17/725544 is withdrawn in view of the amendment to the claims.
The non-statutory double patenting (NSDP) and provisional NSDP rejections of claims 1-23 over copending Applications Nos. 17/702,648, 17/726296, 17/532919, 17/822701, 18/557988, 18/684103, 18/025849 in view of Boghaert et. al., 18/696453, 17/668134, and 18/685667 are withdrawn in view of the amendment to the claims.
Specification- Maintained
The use of the terms Taxotere, Abraxane, Sutent, and Nexavar ([202], [204]) which are trade names or a marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Response to arguments
Although Applicant has amended to include the proper trade mark symbols at [0225], [0226], and [0228] of the specification, the specification still contains improperly identified instances at [202] line 3 and line 6-7 and [204] lines 3 and 6.
Claim Rejections - 35 USC § 112(b)- Maintained, changes necessitated by amendment
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-3, 5, 9, 16, and 24-34 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 is rejected for the recitation of “one or more therapeutically radiolabeled targeting agents”. The metes and bounds of the claim are unclear because “therapeutically radiolabeled” is not defined in the specification or the claim, and it is not clear what would be required for the 5T4 monoclonal antibody or monoclonal antibody fragment to be radiolabeled therapeutically. For the purposes of expedited prosecution, the claim will be interpreted as a referring to a 5T4 antibody or antigen-binding fragment linked to a therapeutically active radiolabel such as described in the Specification para. [0133], for example.
Dependent claims are rejected for failing to resolve the indefiniteness as described.
Response to arguments
Applicant argues that the amendments to claim 1 to recite “therapeutically radiolabeled monoclonal antibody” resolve the indefiniteness as described (Remarks 11/19/2025 p. 9). This is not persuasive because, as described above, it is unclear what the metes and bounds of the term “therapeutically radiolabeled” are because there is no art-recognized definition of “therapeutically radiolabeled”. Because of the instant method of treating cancer, the Examiner thinks that the applicant may mean the monoclonal antibodies radiolabeled with a cytotoxic radioisotope or an ɑ- or β- emitting radionuclide as used in Martins, Carlos Daniel. "Radioimmunotherapy for delivery of cytotoxic radioisotopes: current status and challenges." Expert opinion on drug delivery 15.2 (2018): 185-196, see the introduction. The Applicant must clarify the metes and bounds of what would be considered a “therapeutically radiolabeled” monoclonal antibody.
Claim Rejections - 35 USC § 112(b)- New, changes necessitated by amendment
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 5, 28, and 33 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.
Claims 5, 28, and 33 each recite “a composition of 225Ac-labeled antibody or antibody fragment and non-radiolabeled antibody or antibody fragment, the composition comprising a dose of 0.1-2.0 µCi/kg body weight of the subject and a protein dose of 0.1-5.0 mg/kg body weight of the subject, and the CD47 blockade is administered at a total dose of 0.05-5.0 mg/kg body weight of the subject. This is indefinite because, although the “a composition of 225Ac-labeled antibody or antibody fragment and non-radiolabeled antibody or antibody fragment” is the only composition explicitly recited, it is unclear:
Whether the composition 225-Ac labeled antibody or antibody and non-radiolabeled antibody or antibody fragment refers to the anti-5T4 or anti-HER3 antibodies of the parent claims because the claim recites a generic antibody in the composition. Further, it is unclear if the composition comprises a mix of labeled and unlabeled anti-5T4 and anti-HER3 antibodies, respectively, or if the unlabeled antibody in the composition refers to an antibody that is the CD47-blockade. For example, Vivier, et. al. "Understanding the in vivo fate of radioimmunoconjugates for nuclear imaging." Journal of Labelled Compounds and Radiopharmaceuticals 61.9 (2018): 672-692 teaches that the “binding site barrier” of an antibody from which antibodies that bind with high affinity give rise to a heterogeneous uptake within solid tumors may be overcome by increasing the dose of unlabeled antibody in order to facilitate the saturation of the target in the perivascular space of the tumor (p. 4 ¶2). However, it is unclear what the metes and bounds of the claim are because the claim is directed to any 225Ac labeled and unlabeled antibody composition.
Whether the protein dose of the composition refers to a composition comprising a single monoclonal antibody with both labeled and unlabeled antibodies, and therefore caps the only the dose of the labeled antibody, or whether the “protein dose” also includes the protein CD47 blockade in the upper limit. Although “a composition” is explicitly stated once, claims 1 and 9 upon which the instant claims depend implicitly disclose a composition because they are di This is unclear because the upper limit of the protein dose is 5.0mg/kg, and the upper limit of the CD47 blockade is also 5.0mg/kg. It would imply a composition, therefore, that comprises 0mg/kg of the labeled antibody because the CD47 blockade comprises the entire dose.
The metes and bounds are therefore unclear.
Claim Rejections - 35 USC § 112(a)- New, necessitated by amendment
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3, 5, 9, 16, and 24-34 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 a cancer expressing 5T4 in a mammalian subject comprising administering to a mammalian subject having the cancer comprising administering a radiolabeled monoclonal antibody against 5T4 and administering to the mammalian subject an effective amount of one or more CD47 blockades, wherein the one or more of an blockades comprises one or more of an anti-CD47 antibody, an anti-SIRPɑ antibody, or a SIRPɑ Fc fusion protein and wherein the cancer is colorectal cancer, gastric cancer, ovarian cancer, non-small cell lung carcinoma, head and neck squamous cell cancer, pancreatic cancer, renal cancer, or any combination thereof;
a method of treating a cancer expressing HER3 in a mammalian subject comprising administering to a mammalian subject having the cancer comprising administering a radiolabeled monoclonal antibody against 5T4 and administering to the mammalian subject an effective amount of one or more CD47 blockades, wherein the one or more of an blockades comprises one or more of an anti-CD47 antibody, an anti-SIRPɑ antibody, or a SIRPɑ Fc fusion protein and wherein the cancer is pancreatic cancer, lung cancer, head and neck cancer, breast cancer, gastric cancer, colorectal cancer, esophageal cancer, prostate cancer, or ovarian cancer;
does not reasonably provide enablement for:
the method of treating a cancer in a mammalian subject comprising wherein the cancer is
the method of treating a cancer in a mammalian subject comprising wherein the cancer is not limited by antigen expression, comprising administering a generic HER3-binding monoclonal antibody fragment as recited in claim 9
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the method of the invention commensurate in scope with these claims.
Scope of the claimed genus and nature of the invention
The instant claims are directed towards:
A method of treating cancer from a list of cancer subtypes wherein the cancer is not limited by antigen expression, comprising administering to a mammalian subject having the cancer an effective amount of a therapeutically radiolabeled monoclonal antibody against 5T4 or a therapeutically labeled 5T4-binding monoclonal antibody fragment; and administering to the mammalian subject an effective amount of one or more CD47 blockades, wherein the one or more CD47 blockades comprises one or more of an anti-CD47 antibody, an anti-SIRPɑ antibody, or a SIRPɑ Fc fusion protein
A method of treating cancer from a list of cancer subtypes wherein the cancer is not limited by antigen expression, comprising administering to a mammalian subject having the cancer an effective amount of a therapeutically radiolabeled monoclonal antibody against HER3 or a therapeutically labeled HER3-binding monoclonal antibody fragment; and administering to the mammalian subject an effective amount of one or more CD47 blockades, wherein the one or more CD47 blockades comprises one or more of an anti-CD47 antibody, an anti-SIRPɑ antibody, or a SIRPɑ Fc fusion protein
Regarding claim interpretation, the specification does not define “antibody fragment”.
The broadest reasonable interpretation of the terms “a therapeutically labeled 5T4-binding monoclonal antibody fragment” and “a therapeutically labeled HER3-binding monoclonal antibody fragment” in claims 1 and 9, therefore, includes any fragment of a HER3-binding monoclonal antibody such as a single CDR. The scope of the claims therefore includes antibody fragments with unknown binding activity.
Dependent claims 2-3, 5, 16, and 24-34 do not further limit the scope of the claims in regards to the antigen expression profile of the cancer or the antibody fragments.
State of the Relevant Art; level of ordinary skill; and level of predictability in the art
Regarding methods of treating 5T4-expressing cancer with anti-5T4 antibodies and radionuclide conjugated anti-5T4 antibodies, some of these are known in the art. US 20070231333 A1 to Boghaert et. al. (Of record, PTO-892 5/19/2025) teaches anti-5T4 antibodies including anti-5T4 radioimmunoconjugates for the treatment of cancer ([0002], [210], [121-122]). Harper, Jay, et al. "Preclinical evaluation of MEDI0641, a pyrrolobenzodiazepine-conjugated antibody–drug conjugate targeting 5T4." Molecular Cancer Therapeutics 16.8 (2017): 1576-1587 teaches an additional anti-5T4 immunoconjugate comprising and different anti-5T4 antibody optimized for binding with a pyrrolobenzodiazepine (PDB) dimer or tubulyisin payload (Abstract) that produced anti-tumor responses in tumor xenograft models (Fig. 3).
Regarding methods of treating HER3-expressing cancer with anti-HER3 antibodies and radionuclide conjugated anti-HER3 antibodies, some of these are known in the art. WO2019028555 to Maruthachalam et. al. teaches a method of treating HER3-expressing cancer comprising a conjugated anti-HER3 antibody, wherein the conjugate may be a radionuclide (Abstract, [0031], [00121], [00167]). Mishra, Rosalin, et al. "HER3 signaling and targeted therapy in cancer." Oncology reviews 12.1 (2018): 355 published May 16 2018 teaches additional anti-HER3 ADCs (p. 50 Table 2) in preclinical development for cancer therapy with different antigen binding domains.
None of these antibodies or antibody fragments for the treatment of cancer comprised less than a complete VH and VL domain.
Regarding “CD47 blockade”, blockades of CD47 interaction are known in the art. For example, Maxhimer et al., Radioprotection in Normal Tissue and Delayed Tumor Growth by Blockade of CD47 Signaling. Sci. Transl. Med.1,3ra7-3ra7(2009).DOI:10.1126/scitranslmed.3000139 discloses blockade of CD47 by an anti-CD47 antibody and a CD47-binding peptide (see p. 2 Col. 2, “clone B6H12”, Fig. 1A and B and “7N3”, Fig. 1C) and a CD47 morpholino oligonucleotide (p. 3 Col. 2 “Tissue protection and decreased vasculopathy from radiation injury by antisense CD47 suppression” section, Fig. 4) (Of record, PTO-892 5/19/2025).
It is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro et. al., Front. Immunol. 2018; 8:1751 (see Section “The IgG Molecule” in paragraph 1 and Figure 1) (Of record, PTO-892 5/19/2025). 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, Of record, PTO-892 5/19/2025) 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, the prediction of CDR binding to the epitope is difficult to predict. Chiu further taught antibody modeling has been shown to be accurate for the framework region sequences, but CDR modeling requires further development and improvements (page 6, second paragraph). Prediction of the structure of HCDR3 could not be accurately produced when given the Fv structures without their CDR-H3s (page 6, second paragraph). Chiu taught the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate, and the results of antibody–antigen docking are also disappointing (page 11, paragraph 2).
Antibodies to several different antigens have been in clinical use as cancer therapeutics since the late 1990s (e.g., Reichert & Valge-Archer, Nat. Rev. Drug Disc. 2007; 6:349-356 (see Table 1)). The level of skill in the art is therefore high. But while several antigens had been successfully targeted on cancer cells by therapeutic antibodies, validation of an antigen as a therapeutic target does not validate the use of all antibodies to that target as therapeutics, much less any fragment of the antibody. In particular, it was well known in the art that different antibodies to the same antigen can have different effects following binding of their target antigen. Chan, Andrew C., and Paul J. Carter. "Therapeutic antibodies for autoimmunity and inflammation." Nature reviews immunology 10.5 (2010): 301-316, summarize these different effects in Figure 2. The five distinct mechanisms include ligand blockade, receptor blockade, receptor downregulation, depletion of cells expressing the target, and signaling induction. The first four mechanisms generally act to inhibit the activity of cells expressing the receptor (or ligand counter receptor). Antibodies that function via these mechanism may broadly be considered antagonist antibodies. Antibodies that induce signals (agonist antibodies), however, may induce either positive or negative signals, depending not only on the nature of the target, but also on other factors such as the developmental state of the cell expressing the target. As described above, it would therefore not be determinable a priori that any given fragment of an anti-HER3 or anti-5T4 antibody was cytotoxic, even when conjugated to a cytotoxic radionuclide. In addition, antibodies therapy can be further used immunoconjugates, wherein the antibody is coupled to a cytotoxic moiety such as a drug or radioisotope in order to improve tumor killing over antibody therapy alone. Larson, Steven M., et al. "Radioimmunotherapy of human tumours." Nature Reviews Cancer 15.6 (2015): 347-360 reviews radiotherapy of human tumors and states that cancer selected antibodies are well-suited to conjugation with radioisotopes. Larson et. al. teaches both limitations and success for a variety of anti-tumor antigen antibodies in the treatment of solid tumors (See “RIT of solid tumors” section, p. 354 right column).
As reviewed in Reichert & Valge-Archer (supra), antibodies can mediate an anti-tumor effect by several different mechanisms. e.g., page 350 "Modes of Action." An antibody conjugated to a cytotoxic agent (an antibody-drug conjugate, or “ADC”) kills the tumor cell by a direct effect, as do radiolabeled antibodies. Id., col. 3. However, such immunoconjugates generally require that the antibody used to deliver the toxin/radiolabel be internalized into the tumor cell; and internalization is a property that is not shared by all antibodies, even among antibodies to the same tumor antigen. Id. at page 351, 1st column. Antibodies can also mediate their effect in an “unmodified” form by activating the immune system, either via ADCC, CDC, or direct induction of apoptosis. Id. at "Immune system activation.” But as the review discusses, not all antibodies have these activities, and ADCC and CDC both depend on the antibody isotype as well as the epitope of the antigen bound. Thus, the skilled artisan understood that the particular epitope targeted by the antibody and the form of the antibody were also determinants of therapeutic activity or lack thereof, even for the same target antigen; and that expression of the target antigen on the target cell would be required for each of these methods of cytotoxicity.
It is well established in the art that the testing of antibodies for cancer treatment occur in cell culture and preferably in animal models (HogenEsch, Harm, and Alexander Yu Nikitin. "Challenges in pre-clinical testing of anti-cancer drugs in cell culture and in animal models." Journal of Controlled Release 164.2 (2012): 183-186, abstract). Tumor cell lines provide essential data for determining the impact in unique tumor phenotypes and genotypes and the changes to pathways and DNA from anti-cancer drugs (Page 2 Tissue Culture). Animal models can include Xenograft models allowing for human tumor cells to be injected into an animal model. A key advantage to animal cancer models is the selection in physiologically natural conditions including stromal microenvironments and the immune system (Page 5 in paragraph 2). The development of genetically engineered mice creates mouse models that more closely mimic the human environment (Page 4 in last paragraph).
Summary of Species disclosed in the original specification; the amount of direction provided by the inventor, existence of working examples; and quality of experimentation needed to make or use the invention based on the content of the disclosure
Regarding cancer targeting agents, the instant specification discloses many antibody or peptide radioconjugates against CD33, DR5, 5T4, HER2, HER3, and TROP2 labeled with actinium-225 [0078]. These include lists of art-known antibodies and peptides such as gemtuzumab (anti-CD33) [0085]; tigatuzumab (anti-DR5) [0093]; auristatin and MD106041 (anti-5T4) [0096-0097]; patritumab (anti-HER3) [0102], also see examples in Table 2; Sacituzumab (anti-TROP2) [0126]; 90-Y IMMU-107 (anti-MUC1) [0130]; Rosopatamab (anti-PSMA) [0133].
The specification also discloses that “Those skilled in the art will readily appreciate that given known target protein amino acid sequences, various types of suitable antibodies and antibody mimetics specific for the extracellular domain of HER3, such as of human HER3, for use in the various aspects of the invention, may be produced using immunization and/or panning and/or antibody engineering techniques that are well established in the art” [0122].
The specification also discloses other radiolabeled cancer targeting agents [0134-0159]. In many cases, it is unclear whether these molecules discussed are antibodies, peptides, or another type of targeting agent.
Lastly, the specification discloses radio-labeled phospholipid-based cancer targeting agents, incorporated by reference to U.S. Pub. No. 20200291049 [0160].
Regarding CD47 blockades, the instant specification defines “CD47 blockade” as any agent that reduces the binding of CD47 to SIRPɑ [0185]. These include SIRPɑ-IgG Fc fusion proteins TTI-621 and TTI-622 disclosed in U.S. Patent No. 9969789; antibodies that bind CD47 to block interaction with SIRPɑ such as clone B6H12 [0187] or Hu5F9-G4 [0188]; antibodies that bind SIRPɑ such as ADU-1805 and other examples listing in [0190]; any modulators of CD47 or SIRPɑ expression such as MBT-001 and PMO oligomer CD47 inhibitors disclosed in U.S. Patent Nos. 8236313, 10370439, and WO2008060785; and small molecule inhibitors such as RRx-001 and Azelnidipine [0193]. The instant specification also discloses CD47 blockades from Table 3 [0194]. Even though the number of species described is large, the only working example of a combination therapy administered to cells was the anti-CD47 antibody magrolimab and B6.H12 (Specification Example 8).
Conclusion
Applicant does not have enablement for the full scope of a method of treatment with any therapeutically radiolabeled fragment of a) a 5T4-binding monoclonal antibody or b) a HER3-binding monoclonal antibody, wherein the cancer is selected from a group of cancer subtypes but is not required to express 5T4 or HER3, respectively. It would take undue experimentation to determine a method of treatment in cancers that do not express the target antigen of the radiolabeled monoclonal antibody and to determine the method of treatment with any fragment of the antibody, where binding would be unpredictable, as claimed.
Claim Rejections - 35 USC § 103- Modified and New
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-3 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over US 20070231333 A1 to Boghaert et. al. published 4 October 2007 (Of record, PTO-892 dated 5/19/2025).
Regarding claim 1, Boghaert et. al. discloses a therapeutic composition and method for the treatment of a cancer comprising administering an anti-human 5T4 antibody or antibody-drug conjugate [0002], [210] in combination with a second therapeutic agent [0024]; wherein the anti-5T4 antibody of the invention may comprise a high energy radioisotope that is conjugated to the anti-5T4 antibody and that the anti-5T4 radioisotopes may be suitable for radiotherapy [121-122] and wherein the anti-5T4/drug conjugates may be administered with additional therapeutic agents [0211] such as at least one radiotherapeutic agent and a CD47 blockade via anti-CD47 antibodies [0215]. The anti-5T4 antibody of the radioimmunoconjugate is a monoclonal antibody [0011].
Regarding claims 2-3 and 19-22, Boghaert et. al. discloses that the conjugated radioisotope may be an alpha emitter or a beta emitter [0215].
Regarding claim 7, the monoclonal antibody is an anti-5T4 antibody [0002, 0011, 121-122] and are “agents having anti-cancer activity in 5T4-expressing cells such as cancer cells from squamous/adenomatous lung carcinoma (non-small-cell lung carcinoma), invasive breast carcinoma, colorectal carcinoma, gastric carcinoma, squamous cervical carcinoma, invasive endometrial adenocarcinoma, invasive pancreas carcinoma, ovarian carcinoma, squamous vesical carcinoma, and choriocarcinoma” [0116].
Regarding claims 16, the anti-CD47 antibody is an additional therapeutic agent [0211, 0215] (reads on discrete molecule).
Boghaert does not explicitly teach the method of treating cancer comprising a radiolabeled anti-5T4 antibody in combination therapy, wherein the additional therapeutic agent is the anti-CD47 antibody, and anti-SIRPɑ antibody, or a SIRPɑ Fc fusion protein.
It would have been prima facie obvious for a person of ordinary skill in the art, before the effective filing date, to treat a mammalian subject having cancer with a combination of an anti-5T4 monoclonal antibody conjugated to a high energy radioisotope for the treatment of cancer as taught by Boghaert et. al. in combination with an additional therapeutic agent as taught by Boghaert et. al., wherein the additional therapeutic agent is an anti-CD47 antibody as taught by Boghaert et. al. to benefit from the combination anti-cancer therapy as taught by Boghaert. This would have a reasonable expectation of success because Boghaert teaches the anti-cancer therapy benefits of radionuclide-conjugated 5T4 monoclonal antibodies and anti-CD47 antibodies, and an artisan would expect suitable anti-cancer benefits from using them in combination.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over US 20070231333 A1 to Boghaert et. al. published 4 October 2007 (Of record, PTO-892 dated 5/19/2025) as applied to claim 1 above, and further in view of WO 2019027973 to Sandesh et. al. (Of record, PTO-892 dated 5/19/2025) and US 20170210803 to Willingham et. al. (Of record, PTO-892 dated 5/19/2025).
The teachings of Boghaert et. al. in regards to claim 1 are in the 103 rejection above.
Boghaert discloses that radioisotopes that may be conjugated to the anti-5T4 antibody include 225-Actinium [0122]. Boghaert et. al. also teaches that “an effective dose will be in the range from about 0.01 mg/m2 to about 50 mg/m2, such as from about 0.1 mg/m2 to about 20 mg/m2, or about 15 mg/m2, which dose is calculated based on the amount of anti-5T4 antibody. For a radiolabeled anti-5T4 antibody, an effective dose is typically in the range from about 1 mCi to about 300 mCi, normally about 5 mCi to 100 mCi, depending on the radioisotope and the binding affinity of the antibody” [0207]. Boghaert does not explicitly disclose that a radiation dose of 0.1-2.0 µCi/kg body weight of the subject and a protein dose of 0.1-5.0mg/kg body weight of the subject and wherein the CD47 blockade is administered at a total dose of 0.05-5.0 mg/kg body weight of the subject.
This deficiency is partially resolved by WO2019027973 to Sandesh et. al.
Sandesh et. al. teaches a radionuclide labelled monoclonal antibody and teaches an effective amount of the labeled antibody comprises a radiation dose of 0.1 to 10 0.1-2.0 µCi/kg body weight of the subject [0130] and at dose ranges selected from a group including 1ug/kg to 1mg/kg [129],[0134].
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to use the dosing schedule of Sandesh et. al. to modify the composition of Boghaert for the purpose of developing an effective dose comprising a radiolabeled antibody and a protein concentration specific to the subject. This would have a predictable effect because both Boghaert and Sandesh et. al. teach radiolabeled therapeutic monoclonal antibodies.
Boghaert et. al. in view of Sandesh et. al. does not teach that the CD47 blockade is administered at a total dose of 0.05-5.0 mg/kg body weight of the subject.
This is resolved by Willingham et. al. Willingham et. al. teaches combination treatments of CD47 blockade in combination with an immunomodulatory anti-cancer therapy (Abstract, [0115]), wherein the therapeutic dosage may be about 0.01 to about 5mg/kg of the host body weight [120]. Example dosages can be 1 mg/kg body weight or 10 mg/kg body weight with the range of 1-10 mg/kg [120].
It would have been prima facie obvious for a person of ordinary skill in the art, before the effective filing date, to optimize the anti-CD47 blockade dose within the disclosed preferred range of about 0.1 to about 5mg/kg or 1-10mg/kg body weight in a combination therapy with a second monoclonal antibody in order to determine the effective dose in combination with a second antibody at less than 1mg/kg body weight to predictable effect because both Boghaert and Willingham teach combination antibody therapies comprising anti-CD47 antibodies. See MPEP §2144.05.
Claims 9, 24-27, and 29 are rejected under 35 U.S.C. 103 as being unpatentable over WO2019028555 to Maruthachalam et. al. published 14 February 2019 in view of U.S. 20180251558 to Maute et. al. published 8 September 2018 as evidenced by Cruz-Nova, Pedro, et al. "Radiobiological effect of alpha particles. The scientific basis of targeted alpha-particle therapy." Nuclear Medicine and Biology 146 (2025): 109044 and Behr, Thomas M., et al. "High-linear energy transfer (LET) α versus low-LET β emitters in radioimmunotherapy of solid tumors: therapeutic efficacy and dose-limiting toxicity of 213Bi-versus 90Y-labeled CO17-1A Fab′ fragments in a human colonic cancer model." Cancer research 59.11 (1999): 2635-2643.
Regarding claims 9 and 25, Maruthachalam et. al. teaches a therapeutic composition and a method of treatment of HER3-expressing cancer comprising administering an effective amount of an immunoconjugate to a subject in need thereof, wherein the HER3 expressing cancer is breast cancer, gastric cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, or colon cancer (Abstract, [0031], [00167]). In one embodiment, the animal is a mammal or a human [00169]. The immunoconjugate comprises an anti-HER3 monoclonal antibody or antigen-binding fragment thereof ([0006],[0098]). One embodiment of the immunoconjugate is the anti-HER3 antibody conjugated to a cytotoxic radionuclide [00121].
Regarding claim 26, Maruthachalam et. al. teaches the radionuclides may be selected from a group including 212Bi [00121], which is an alpha-particle emitting radionuclide (as evidenced by Cruz-Nova, Pedro, et al. see p. 2 left column ¶3). Regarding claim 27, teaches the radionuclides may be selected from a group including 90Y [00121], which is a beta-particle emitting radionuclide (as evidenced by Behr, Thomas M., et al., Abstract).
Maruthachalam et. al. does not teach a method of treating one of the recited cancer subtypes comprising administering to a mammal an anti-HER3 monoclonal antibody conjugated to a cytotoxic radionuclide, comprising administering to the mammalian subject an effective amount of one or more CD47 blockades, wherein the one or more CD47 blockades comprises one or more of an anti-CD47 antibody, an anti-SIRPɑ antibody, or a SIRPɑ Fc fusion protein.
This deficiency is resolved by Maute et. al.
Maute et. al. teaches a method of inducing phagocytosis of a target cell and treating an individual having cancer comprising administering an anti-CD47/SIRPɑ agent in combination with an agent that potentiates activity or otherwise increases therapeutic effect by co-administration of an anti-class I/LILRB1 agent, an agent the opsonizes a target cell, and an anti-CD47/SIRPɑ agent [160]. The agent that opsonizes a target cell is any agent that can bind to a target cell (e.g. a cancer cell) and opsonize a target cell. Example agents are monoclonal antibodies for the treatment of solid tumors, for example Cetuximab (anti-EGFR) and Trastuzumab (anti-HER2) [0163]. In exemplary embodiments, the anti- CD47/SIRPɑ agent is the anti-CD47 antibody Hu5F9-G4 ([0015], [0104], [0112]). Maute et. al. teaches that the combinations with the highest phagocytosis against breast cancer cell lines are combinations including traditional anti-cancer monoclonal antibodies (cetuximab, trastuzumab, and panitumumab) and the anti-CD47 5F9-G4 compared to the traditional monoclonals alone (Fig. 17).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to use the anti-HER3 radionuclide immunoconjugate of Maruthachalam et. al. as an additional therapeutic in combination with the anti-CD47 antibody combination therapy of Maute et. al. in order to benefit from the additional anti-cancer phagocytosis benefits as taught by Maute et. al and to increase the breadth of cancer antigens targeted as suggested by Maute et. al. This would have a reasonable expectation of success because Maute et. al. suggest that any antibody that targets and opsonizes the cancer cell such as a monoclonal antibody targeting cancer antigens EGFR and HER is suitable in combination to induce phagocytosis, and therefore an artisan would understand that other cytotoxic anti-cancer agents such as the anti-HER3 radionuclide immunoconjugate of Maruthachalam et. al. would be similarly suitable opsonization agents.
Regarding claims 24 and 29, the modified method of Maute and Maruthachalam et. al. as described above teaches that the anti-CD47 antibody and the anti-HER3 antibody are discrete antibodies.
Claim 28 is rejected under 35 U.S.C. 103 as being unpatentable over WO2019028555 to Maruthachalam et. al. published 14 February 2019 in view of U.S. 20180251558 to Maute et. al. published 8 September 2018 (Of record, PTO-892 dated 5/19/2025) as applied to claims 9 and 25 above, and further in view of Song, Hong, et al. "Radioimmunotherapy of breast cancer metastases with α-particle emitter 225Ac: comparing efficacy with 213Bi and 90Y." Cancer research 69.23 (2009): 8941-8948; WO 2019027973 to Sandesh et. al. (Of record, PTO-892 dated 5/19/2025); and US 20170210803 to Willingham et. al. (Of record, PTO-892 dated 5/19/2025).
The teachings of Maruthachalam et. al. and Maute et. al. in regards to claims 9 and 25 are in the 103 rejection above.
Maruthachalam et. al. and Maute et. al. do not teach the method wherein the method comprises administering a composition 225Ac tagged monoclonal antibody and a radiation dose of 0.1-2.0 µCi/kg body weight of the subject and a protein dose of 0.1-5.0mg/kg body weight of the subject and wherein the CD47 blockade is administered at a total dose of 0.05-5.0 mg/kg body weight of the subject.
This deficiency is partially resolved by Song et. al.
Song et. al. teaches that a 225-Ac conjugated anti-HER2 antibody more significantly prolonged lifespan in mouse models of NT2.5 cancer mouse models in vivo compared to Bi-213 and Y-90 (Fig. 2) on both early-treated and late stage metastases of the model (See Fig. 2C and Fig. 3). Song et. al. teaches “The improved efficacy of α-emitter 225Ac over 213Bi and 90Y can partially be attributed to the higher radiation doses that micrometastases receive from 225Ac. 225Ac emits four α-particles along its decay chain and deposits a total energy of 4.50 × 10−12 J/Bq s, 3.2 and 30.0 times higher than that by 213Bi and 90Y. Furthermore, the majority of α-radiation will be absorbed locally, whereas most of the β-particle energy from 90Y will be deposited outside of micrometastases”.
It would have been obvious for a person of ordinary skill in the art to use a cytotoxic radionuclide anti-HER3 immunoconjugate as taught by modified Maruthachalam et. al. and Maute et. al. substituted with the 225Ac radionuclide of Song et. al. in order to benefit from the higher anti-cancer and anti-metastasis cytotoxicity with 225Ac as compared to other radionuclides as taught by Song et. al. This would have a reasonable expectation of success because an Maruthachalam et. al. teaches that many different cytotoxic radionuclides are acceptable and an artisan would expect that the 225Ac would have a similar anti-metastasis effect when conjugated with a HER2 antibody as with a HER3 antibody.
Modified Maruthachalam et. al. and Maute et. al. in view of Song et. al. does not teach the specific radiation and protein doses of the combination therapy are 0.1-2.0µCi/kg body with of the subject 0.1-5.0mg/kg body weight of the subject, respectively, and the CD47 blockade is at a total dose of 0.05-5.0mg/kg body weight of the subject.
This deficiency is partially resolved by WO2019027973 to Sandesh et. al.
Sandesh et. al. teaches a 225-Ac radionuclide labelled monoclonal antibody and teaches an effective amount of the labeled antibody comprises a radiation dose of selected from a group of ranges including 0.1-2.0 µCi/kg body weight of the subject [0130] and at dose ranges selected from a group including 100ug/kg to 1mg/kg [129],[0134].
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to use the dosing schedule of Sandesh et. al. to modify the composition of Maruthachalam et. al. and Maute et. al. in view of Song et. al. for the purpose of developing an effective dose comprising a radiolabeled antibody and a protein concentration specific to the subject. This would have a predictable effect because both Maruthachalam et. al. and Maute et. al. in view of Song et. al. and Sandesh et. al. teach radiolabeled therapeutic monoclonal antibodies and an artisan would expect to be able to optimize the most effect dose of 225-Ac labeled antibody for both radiation and protein dosing.
Modified Maruthachalam et. al. and Maute et. al. in view of Song et. al. in view of Sandesh et. al. does not teach that the CD47 blockade is administered at a total dose of 0.05-5.0 mg/kg body weight of the subject.
This is resolved by Willingham et. al. Willingham et. al. teaches combination treatments of CD47 blockade in combination with an immunomodulatory anti-cancer therapy (Abstract, [0115]), wherein the therapeutic dosage may be about 0.01 to about 5mg/kg of the host body weight [120]. Example dosages can be 1 mg/kg body weight or 10 mg/kg body weight with the range of 1-10 mg/kg [120].
It would have been prima facie obvious for a person of ordinary skill in the art, before the effective filing date, to optimize the anti-CD47 blockade dose within the disclosed preferred range of about 0.01 to about 5mg/kg or 1-10mg/kg body weight in a combination therapy with a second monoclonal antibody in order to determine the effective dose in combination with a second antibody at less than 1mg/kg body weight to predictable effect because both Boghaert and Willingham teach combination antibody therapies comprising anti-CD47 antibodies. See MPEP §2144.05.
Claims 30-32 and 34 are rejected under 35 U.S.C. 103 as being unpatentable over WO2019028555 to Maruthachalam et. al. published 14 February 2019 in view of U.S. 20180251558 to Maute et. al. published 8 September 2018 (Of record, PTO-892 dated 5/19/2025) as applied to claim 9 above, and further in view of Mishra, Rosalin, et al. "HER3 signaling and targeted therapy in cancer." Oncology reviews 12.1 (2018): 355 published May 16 2018 and US 20170210803 to Willingham et. al. (Of record, PTO-892 dated 5/19/2025) as evidenced by Cruz-Nova, Pedro, et al. "Radiobiological effect of alpha particles. The scientific basis of targeted alpha-particle therapy." Nuclear Medicine and Biology 146 (2025): 109044 and Behr, Thomas M., et al. "High-linear energy transfer (LET) α versus low-LET β emitters in radioimmunotherapy of solid tumors: therapeutic efficacy and dose-limiting toxicity of 213Bi-versus 90Y-labeled CO17-1A Fab′ fragments in a human colonic cancer model." Cancer research 59.11 (1999): 2635-2643.
The teachings of Maruthachalam et. al. in view of Maute et. al. are in regards to claim 9 are in the 103 rejection above.
Regarding claim 31, Maruthachalam et. al. teaches the radionuclides may be selected from a group including 212Bi [00121], which is an alpha-particle emitting radionuclide (as evidenced by Cruz-Nova, Pedro, et al. see p. 2 left column ¶3). Regarding claim 32, Maruthachalam et. al. teaches the radionuclides may be selected from a group including 90Y [00121], which is a beta-particle emitting radionuclide (as evidenced by Behr, Thomas M., et al., Abstract).
Regarding claim 34, the modified method of Maute and Maruthachalam et. al. as described above teaches that the anti-CD47 antibody and the anti-HER3 antibody are discrete antibodies.
Modified Maruthachalam et. al. in view of Maute et. al. does not teach the method wherein the cancer is prostate cancer.
This deficiency is resolved by Mishra and Willingham et. al.
Mishra teaches that increased HER3 expression is associated with ovarian, breast, prostate, gastric, bladder, lung, melanoma, colorectal and squamous cell cancers (p. 46, left column). Mishra et. al. teaches that elevated expression of HER3 in castration-resistant prostate cancer leads to activation of PI3K/AKT signaling and androgen receptor stabilization (p. 46, right column). Mishra et. al. teaches that there are anti-HER3 antibodies and anti-HER3 antibody drug conjugates in preclinical development for prostate cancer (Table 1, see p. 49 “MP-RM-1”; “EV20” and Table 2 p. 50 “Anti-HER3 ADCs).
Willingham et. al. teaches a combination therapy of anti-CCR2 with CD47 blockade for CCR2 positive cells such as prostate cancer [0071] and teaches methods for depletion of cancer cells using CD47 blockade therapy [0091] wherein the cancers are selected from a large list of types including prostate cancer [0089].
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform the method of treating with a combination of a radionuclide-conjugated anti-HER3 antibody and an anti-CD47 antibody of Maruthachalam et. al. and Maute et. al. as described in the 103 above in a method of treating prostate cancer to benefit from expanding the treatment group to include an additional high-HER3 expressing cancer as taught by Mishra. This would have a reasonable expectation of success because Mishra teaches the preclinical application of anti-HER3 antibodies including ADCs for prostate cancer therapy and Willingham teaches a combination of CD47 blockade and a second therapeutic (anti-CCR2, also expressed on prostate cancer as taught by Willingham et. al.). Therefore, an artisan would reasonably predict that a combination therapy on anti-CD47 expected to work in prostate cancer and an anti-HER3 antibody-radionuclide conjugate expected to target HER3-positive prostate cancer cells would be expected to successfully treat prostate cancer.
Claim 33 is rejected under 35 U.S.C. 103 as being unpatentable over WO2019028555 to Maruthachalam et. al. published 14 February 2019 in view of U.S. 20180251558 to Maute et. al. published 8 September 2018; Mishra, Rosalin, et al. "HER3 signaling and targeted therapy in cancer." Oncology reviews 12.1 (2018): 355 published May 16 2018; and US 20170210803 to Willingham et. al. (Of record, PTO-892 dated 5/19/2025), as applied to claim 30 above, and in further view of Song, Hong, et al. "Radioimmunotherapy of breast cancer metastases with α-particle emitter 225Ac: comparing efficacy with 213Bi and 90Y." Cancer research 69.23 (2009): 8941-8948 and WO 2019027973 to Sandesh et. al. (Of record, PTO-892 dated 5/19/2025).
The teachings of Maruthachalam et. al., Maute et. al., Mishra, and Willingham et. al. as applied to claim 30 are in the 103 rejection above.
Regarding claim 33, Willingham et. al. further teaches combination treatments of CD47 blockade in combination with an immunomodulatory anti-cancer therapy (Abstract, [0115]), wherein the therapeutic dosage may be about 0.01 to about 5mg/kg of the host body weight [120]. Example dosages can be 1 mg/kg body weight or 10 mg/kg body weight with the range of 1-10 mg/kg [120].
It would have been prima facie obvious for a person of ordinary skill in the art, before the effective filing date, to optimize the anti-CD47 blockade dose within the disclosed preferred range of about 0.1 to about 5mg/kg or 1-10mg/kg body weight in a combination therapy with a second monoclonal antibody in order to determine the effective dose in combination with a second antibody at less than 1mg/kg body weight to predictable effect because both Boghaert and Willingham teach combination antibody therapies comprising anti-CD47 antibodies. See MPEP §2144.05.
Maruthachalam et. al., Maute et. al., Mishra, and Willingham et. al. do not teach wherein the composition comprises a 225-Ac labeled antibody or antibody fragment, the composition comprising a radiation dose of 0.1-2.0 µCi/kg body weight of the subject and a protein dose of 0.1-5.0mg/kg body weight of the subject.
This deficiency is resolved by Song et. al. and Sandesh et. al.
Song et. al. teaches that a 225-Ac conjugated anti-HER2 antibody more significantly prolonged lifespan in mouse models of NT2.5 cancer mouse models in vivo compared to Bi-213 and Y-90 (Fig. 2) on both early-treated and late stage metastases of the model (See Fig. 2C and Fig. 3). Song et. al. teaches “The improved efficacy of α-emitter 225Ac over 213Bi and 90Y can partially be attributed to the higher radiation doses that micrometastases receive from 225Ac. 225Ac emits four α-particles along its decay chain and deposits a total energy of 4.50 × 10−12 J/Bq s, 3.2 and 30.0 times higher than that by 213Bi and 90Y. Furthermore, the majority of α-radiation will be absorbed locally, whereas most of the β-particle energy from 90Y will be deposited outside of micrometastases”.
It would have been obvious for a person of ordinary skill in the art to use a cytotoxic radionuclide anti-HER3 immunoconjugate as taught by modified Maruthachalam et. al., Maute et. al., Mishra, and Willingham et. al. substituted with the 225Ac radionuclide of Song et. al. in order to benefit from the higher anti-cancer and anti-metastasis cytotoxicity with 225Ac as compared to other radionuclides as taught by Song et. al. This would have a reasonable expectation of success because an Maruthachalam et. al. teaches that many different cytotoxic radionuclides are acceptable and an artisan would expect that the 225Ac would have a similar anti-metastasis effect when conjugated with a HER2 antibody as with a HER3 antibody.
Sandesh et. al. teaches a 225-Ac radionuclide labelled monoclonal antibody and teaches an effective amount of the labeled antibody comprises a radiation dose of 0.1 to 10 0.1-2.0 µCi/kg body weight of the subject [0130] and at dose ranges selected from a group including 1ug/kg to 1mg/kg [129],[0134].
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to use the dosing schedule of Sandesh et. al. to modify the composition of Maruthachalam et. al., Maute et. al., Mishra, Willingham et. al., and Song et. al. for the purpose of developing an effective dose comprising a radiolabeled antibody and a protein concentration specific to the subject. This would have a predictable effect because both Boghaert and Sandesh et. al. teach radiolabeled therapeutic monoclonal antibodies.
Response to Arguments
Applicant’s arguments filed 19 November 2025 have been fully considered but are not persuasive. Applicant argues that Boghaert does not teach each and every limitation of the amended claims because “Boghaert makes no mention of a therapeutically radiolabeled monoclonal antibody against 5T4 or a therapeutically radiolabeled 5T4-binding monoclonal antibody fragment” (Remarks 11/19/2025 p. 9 bottom-p. 10 top). As described in the new 103 rejection, necessitated by amendment, this is not true. Boghaert specifically discloses an anti-5T4 immunoconjugate wherein the immunoconjugate is linked to a radionuclide suitable for radiotherapy and recites administration of the immunoconjugate in a method of treating cancer ([0121-0122]). Boghaert therefore makes obvious the instantly amended claims as described in the 103 rejection of claim 1-3, 16, and of claim 5, above.
Double Patenting- New, necessitated by amendment
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3, 5, 9, 16, and 24-29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 2-5, 7, 9, 20, 21, 23, and 32 of copending Application No. 17725544 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of '544 application make obvious the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 2 and 3 of the ‘544 application recites a method for treating a cancer or precancerous proliferative disorder in a mammalian subject comprising administering an effective amount of one or more therapeutically radiolabeled cancer targeting agents and administering to the mammalian subject an effective amount of one or more CD47 blockades, wherein the CD47 blockades are selected from a group including anti-CD47 antibody, anti-SIRPɑ antibody, SIRPɑ Fc fusion protein, wherein at least one of the radiolabeled cancer targeting agents is labeled with an alpha particle admitting radionuclide (claim 2) or a beta particle emitting radionuclide (claim 3). Claim 4 teaches that the cancer targeting agents are selected from a group including a monoclonal antibody against 5T4 and a monoclonal antibody against HER3. Claim 5 recites that the radiolabeled cancer targeting antigens comprise a composition of 225Ac labeled antibody and non-radiolabeled antibody, the composition comprising a radiation dose of 0.1-2.0µCi/kg body weight of the subject and a protein dose of 0.1-5.0mg/kg body weight of the subject and/or the CD47 blockade is administered at a total dose of .05-5.0mg/kg body weight of the subject. Claims 7 and 23 recite wherein the antibody is an anti-5T4 antibody and the cancer is selected from a group including colorectal cancer, gastric cancer, ovarian cancer, etc. Claim 9 and 21 recite wherein the monoclonal antibody is an anti-HER3 antibody and the cancer or precancerous proliferative disorder is pancreatic, lung, head and neck, breast, etc. Claims 20 and 32 recites wherein the CD47 blockade is a discrete molecule from the therapeutically radiolabeled cancer targeting agent.
Although the claims are not identical, it would have been obvious for a person of skill in the art to arrive at the instantly claimed methods because the claims of ‘544 teach all of the limitations of the instant claims and therefore the methods are not patentably distinct.
Claims 30-44 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 2-5, 7, 9, 20, 21, 23, and 32 of copending Application No. 17725544 (reference application) as applied to claim 9 above and further in view of Mishra, Rosalin, et al. "HER3 signaling and targeted therapy in cancer." Oncology reviews 12.1 (2018): 355 published May 16 2018.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The teachings of claims 2-5, 7, 9, 20, 21, 23, and 32 of the ‘544 application are in the NSDP rejection above.
The claims of the ‘544 application do not teach the method comprising a therapeutically labeled monoclonal antibody against HER3 as in instant claims 30-34, wherein the cancer is prostate cancer.
The teachings of Mishra are in the 103 rejection above. Briefly, Mishra teaches prostate cancer methods of treating cancer comprising anti-HER3 monoclonal antibodies and antibody-drug conjugates.
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to substitute the patient population of the ‘544 claims with the patient population with HER3-expressing prostate cancer to benefit from an improved prostate cancer treatment expected to be effective on a HER3-expressing cancer as taught by Mishra and to expand the candidate patient population of the claim of ‘544. This would have a predictable effect because an artisan would expect from Mishra that an anti-HER3 treatment would be effective for prostate cancer, and from the ‘544 claims that the instant combination of radionuclide-labeled HER3 and anti-CD47 antibody is cytotoxic against multiple types of cancer expressing HER3.
Claims 9 and 24-34 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of copending Application No. 17/532919 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because both applications claim a method of treating cancer with a combination of radiolabeled targeting agent specific for HER3 and CD47 blockades. The ‘919 claims the same combination of an anti-HER3 conjugated to a radionuclide and an CD47 blockade, wherein the CD47 blockade is selected from a group that includes the anti-CD47 monoclonal antibody magrolimab in claims 16 and 19 as in instant claims 4 and 9. Claim 8 recites wherein the solid cancer is breast cancer, gastric cancer, cervical cancer, prostate cancer, among others. Regarding the alpha and beta emitters of instant claims, the list of types of emitters of ‘296 claim 2 contain both alpha and beta emitting radionuclides. Therefore, the scope of the protection sought overlaps, rendering the claims patentably indistinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-3, 5, and 16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-73 of copending Application No. 18/025849 (reference application) in view of US 20070231333 A1 to Boghaert et. al. published 4 October 2007.
Although the claims at issue are not identical, they are not patentably distinct from each other because both applications claim a method of treating cancer with a combination of radiolabeled 5T4 monoclonal antibody and anti-CD47 blockade claim in overlapping particular radiation and protein dose ranges with the instant claims (claim 50-51, radiation dose, claim 22). The ‘849 claims a combination of an anti-cancer associated antigens conjugated to a radionuclide and an CD47 blockade in claims 55 as in instant claims 4 and 7. Additionally, while the claims of ‘849 do not recite the types of cancers treated by the combination therapy, it would have been obvious to treat the types of cancers expressing the 5T4 of claim 5 with the combination therapies of ‘849 claims 55 as recited in ‘849 claim 42 for the anti-5T4 monotherapy. Regarding the alpha and beta emitters of instant claims, the list of types of emitters of ‘849 claim 7 contain both alpha and beta emitting radionuclides.
The ‘849 claims do not teach that the CD47 blockade comprises an anti-CD47 antibody, an anti-SIRPɑ antibody, a SIRPɑ Fc fusion protein.
This deficiency is resolved by Boghaert et. al. Boghaert et. al. discloses an anti-CD47 blockade comprising an anti-CD47 antibody [0215].
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to use the anti-CD47 antibody in the CD47 blockade of the claims of ‘849 because an artisan would look to existing methods of CD47 blockade in order to treat with the combination of the ‘849 claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 9 and 24-34 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-41 of copending Application No. 18/696453 (reference application) in view of Mishra, Rosalin, et al. "HER3 signaling and targeted therapy in cancer." Oncology reviews 12.1 (2018): 355 published May 16 2018.
Although the claims at issue are not identical, they are not patentably distinct from each other because both applications claim a method of treating cancer with a combination of radiolabeled targeting agent specific for a cancer-associated antigen GRP78 and CD47 blockades, further comprising a therapeutically effective amount of a radiolabeled HER3 targeting agent, wherein the radiolabel is selected from a group including 225Ac and the HER3 cancer includes prostate cancer, breast cancer, ovarian cancer, among others. Claim 27 teaches the anti-CD47 blockade includes the anti-CD47 antibody magrolimab. Regarding the alpha and beta emitters of instant claims, the list of types of emitters of ‘103 claims 1-5, 7, 9, and 11 contain both alpha and beta emitting radionuclides.
The claims do not teach wherein the combination therapy comprising the anti-HER3 targeting agent is an anti-HER3 monoclonal antibody and comprises administering at a radiation dose of 0.1-2.0µCi/kg body weight and a protein dose of 0.1-5.0mg/kg body weight, and wherein the CD47 blockade is administered at a total dose of 0.05-5.0mg/kg body weight of the subject.
Claim 21 teaches the radiolabeled anti-GRP78 is a 225Ac labeled targeting agent administered at a protein or peptide dose of less than 3mg/kg subject body weight and a radiation dose selected from a group including 0.1 to 5µCi/kg body weight.
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to optimize the dose of the combination therapy of the anti-GRP78 radionuclide in combination with the anti-HER3 radionuclide and anti-CD47 antibody based on the known protein doses and radiation doses of the 225Ac anti-GRP78 targeting agent.
The claims do not teach the anti-HER3 targeting agent is a monoclonal antibody.
As described in the 103 above, Mishra teaches prostate cancer methods of treating cancer comprising anti-HER3 monoclonal antibodies and antibody-drug conjugates.
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, use an anti-HER3 monoclonal antibody as taught by Mishra et. al. as the anti-HER3 cancer targeting agent in order to have a specific embodiment of a HER3-cancer targeting agent that can be conjugated with the radionuclide. This would have a reasonable expectation of success because an artisan would understand that the anti-HER3 antibody drug conjugates of Mishra suggest that the antibodies can work as immunoconjugates and therefore could be conjugated with a radionuclide as taught by the claims of ‘453.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to arguments
Applicant requests that the double patenting rejections be held in stayed pending the final disposition of the claims (Remarks p. 11). A request to hold a rejection in abeyance is not a proper response to a rejection. Rather, a request to hold a matter in abeyance may only be made in response to an OBJECTION or REQUIREMENTS AS TO FORM (see 37 CFR 1.111(b) and MPEP §714.02). Additionally, MPEP §804.I.B.1 does not allow non-statutory double patenting rejections to be held in abeyance. Thus, the double patenting rejections of record are new or modified as necessitated by amendment as no response to these rejections has been filled by applicant at this time.
Conclusion
No claims are allowed.
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/KATHLEEN CUNNINGCHEN/Examiner, Art Unit 1646
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678