DETAILED ACTION
Current claims 1-3, 5-7, 11-15, 17-20, 22-23, 26, 28, and 42 are currently pending and under examination within this 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 .
Priority
The present application claims benefit from PCT/US2022/012982 which claims benefit from provisional application 63/138,972. The present claims have been reviewed with the prior application and the subject matter of all claim limitations are contained within the prior applications. Therefore, the present application is granted priority under the specified applications and the effective filing date of 1/19/2021.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3, 5-7, 11-15, 18-20, 22-23, 26, 28, and 42 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. This is a written description rejection.
In regard to claims 1 and 42, the claims recite, “a method for treating or preventing bone tumors in a subject comprising administering to the subject an effective amount of a bone-targeting conjugate comprising bisphosphonate (BP) conjugated to,” with claim 1 further reciting ‘an antibody” and claim 42 further reciting “one or more polypeptides.” The recitation of treating and preventing bone cancer or metastasis using an antibody or polypeptide is a broad genus not supported through the disclosure of the application.
An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). Claims 1 and 42 present the broad genus of a bisphosphonate conjugated to “an antibody” or “a polypeptide.” However, the disclosure only describes the use of alendronate-trastuzumab conjugate in treating bone cancer or bone metastasis with no evidence of any other combination of antibody conjugates considered.
Immunotherapy using antibodies has been widely used in oncology treatments. It is known that antibodies bind specifically to their target with minimal non-specific binding. This has led to the FDA approving at least one antibody drug for every known tumor possessing a particular genetic makeup. (Dobosz, P., et al., (2019). Frontiers in Immunology. 10(2965).) The specific nature of antibody therapy requires a specific targeted antibody or protein to treat or prevent a certain type of cancer. The present specification provides evidence that the alendronate-trastuzumab conjugate has been studied and used by the applicant (See Section IV. Examples pgs. 33-48). However, there is no further evidence of a broader genus of BP conjugated to any other antibodies or proteins for treating bone tumors. Therefore, claims 1 and 42 lack written description to claim a BP conjugated to ‘an antibody” or “a polypeptide” as presented in these claims.
Further, claims 13-15 lack written description based on their dependency on claim 1 and their failure to further provide support to overcome a written rejection. Claim 13 recites specific antibodies defined by their binding target and claim 14 recites specifically, anti-HER2 antibodies. Claim 15 further recites the specific antibodies trastuzumab, pertuzumab, or atezolizumab.
As mentioned above, the specification does provide ample support for trastuzumab, which is an anti-HER2 antibody. However, trastuzumab is not entirely representative of all anti-HER2 antibodies. As is evidenced in Richard, trastuzumab and pertuzumab present different modes of action in targeting HER2. (Richard, S., et al, (2015) Annals of the Brazilian Academy of Sciences, 88(S1): pg. 88-89). Pertuzumab acts by inhibiting heterodimerization of HER2 with EGFR, HER3, and HER4. (Richard, pg. 88). While trastuzumab acts against HER2 homodimers. (Richard, pg. 88). While these modes of action could be beneficial to one another, there is no evidence provided within the disclosure that pertuzumab has been used within bone metastasis to treat bone cancer or metastasis.
Further, atezolizumab is a PD-L1 antibody that at the time of the effective filing date was still under exploration for its effect on HER2 breast cancer and had not been approved and recommended for guidelines. (Li, X., et al. (2020). Ann. Transl. Med. 8(24):1634.) With no further disclosure in the present application, claim 15 lacks adequate written description to support the use of pertuzumab and atezolizumab in the treatment or prevention of bone cancer or metastasis.
In regards to claims 2-3, 5-7, 11-12, 18-20, 22-23, 26, and 28 the claims are rejected under written description based on dependency and their failure to provide any subject matter that would overcome the written description.
Claims 1-3, 5-7, 11-15, 17-20, 22-23, 26, 28, and 42 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 enablement requirement. Claims 1 and 42 recite the use of a bisphosphonate conjugated to ‘an antibody” in claim 1 and “one or more polypeptides” in claim 42 in treating or preventing bone tumors (claim 1) or bone diseases (claim 42). The claims contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The present claims are drawn to a method of treating and preventing bone tumors (claim 1) or bone diseases (claim 42) by administering to a subject an effective amount of a bone-targeting conjugate comprising a bisphosphonate conjugated to either an antibody (claim 1) or one or more polypeptides (claim 42). However, the specification does not provide a sufficient enabling description for the treatment of bone tumors using “an antibody” or “bone disease” using “one or more polypeptides.” Without undue experimentation, the present specification does not provide sufficient evidence that an antibody or one or more polypeptides conjugated to a bisphosphonate can be used to treat bone tumors or bone diseases.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). The factors most relevant to the rejection of the present claims are the breadth of the claims, the nature of the invention, the state of the prior art, the level of predictability in the art, the amount of direction provided by the inventor, and the existence of working examples.
The breadth of the claims and the nature of the invention does not enable the present invention. Using the broadest reasonable interpretation (BRI), claims 1 would apply to the use of any antibody to treat or prevent bone tumors. Similarly, using BRI to claim 42 would apply the use of any polypeptide to treat or prevent bone diseases. In the context of this interpretation, the nature of the invention would require a person of ordinary skill in the art to be able to use any antibody or polypeptide to treat and prevent bone tumors or bone diseases to enable the invention. As the specification lists only 3 exact antibodies and provides evidentiary support for only one of them, the application is not properly enabled for one of ordinary skill in the art to make or use the present claimed invention.
Evidence regarding the state of the art and the level of predictability in the art lead to the conclusion that the present invention is not enabled. As evidenced in Dobosz, antibody-based therapies targeting malignant cells contain different modes of action including preventing an antigen from attaching to its receptor or marking an antigen to be destructed. (Dobosz, pg. 3). Further, antibodies represent a very specific targeted therapy where the genetic makeup of the tumor cell identifies the treatment, as opposed to the traditional model using the tissue-of-origin. (Dobosz, pg. 4). This would indicate that an antibody or polypeptide used to treat a bone tumor would require specific identified targets.
As evidenced by the disclosure in the specification, the amount of direction provided by the inventor and the existence of working examples does not enable one of ordinary skill in the art to make or use the present claimed invention. As discussed prior, the specification discloses the use of an alendronate-trastuzumab conjugate in treating bone metastasis. However, the state of the art would not apply a working example of one conjugated antibody that is specific for HER2 to be applied as enabling all antibodies or polypeptides.
Therefore, a person of ordinary skill in the art would not be enabled to make or use the present claimed invention without undue experimentation because the disclosure does not sufficiently describe how to make an antibody or polypeptide that could be conjugated to treat and prevent bone tumors or bone diseases.
Further, claims 1 and 42 lack enablement due to the recitation of the word “preventing.” The method claimed recites the bisphosphonate antibody conjugate as preventing bone tumors (claim 1) or bone disease (claim 42). The specification provides no definition for what it means for the polypeptide conjugate to prevent a bone tumor or bone disease. Applying the broadest reasonable interpretation of the claim, the present invention requires preventing any bone tumor (claim 1) or bone disease (claim 42) from developing to be enabled.
The specification provides no evidentiary support that even the working example disclosed of alendronate-trastuzumab is able to prevent any bone tumor from developing, only bone tumors associated with metastatic HER2+ cancer. Additionally, the specification defines bone disease as consisting of osteoporosis, osteomalacia, periodontis, rheumatoid arthritis, metabolic bone disease, a parathyroid disorder, steroid-induced osteoporosis, chemotherapy-induced bone loss, pre-menopausal bone loss, fragility and recurrent fractures, renal osteodystrophy, bone infections, or Paget's disease. The alendronate-trastuzumab disclosed through the specification was tested using a tumor xenograft model (pg. 35, line 2), a bone micrometastasis model (pg. 35, lines 10-11), and in tumor-induced osteolytic bone destruction (pg. 37 line 19). The evidence provided through the specification only indicates that the working model of alendronate-trastuzumab is able to effect tumor-induced bone destruction. No further evidence is provided to show the ability of the working example to treat bone diseases as defined by the specification, shown above.
As discussed above, the breadth of the claims, the nature of the invention, the state of the prior art, the level of predictability in the art, the amount of direction provided by the inventor, and the existence of working examples apply to the enabling the method for the prevention of bone tumors. Therefore, a person of ordinary skill in the art would not be enabled to make or use the claimed invention in preventing bone tumors or bone diseases without undue experimentation.
It is noted that claim 17 would allow for the enablement rejection to be overcome in regards to the antibody-bisphosphonate conjugate to treat bone tumors. However, it does not overcome the enablement rejection in regards to “preventing” bone tumors. Therefore, claim 17 is rejected based on its dependency on claim 1 and its failure to overcome the enablement rejection as a whole.
Claims 2-3, 5-7, 11-15, 18-20, 22-23, 26, and 28 are rejected based on their dependency on claim 1 and their failure to overcome the enablement rejection.
Claim Objection
Claim 17 is objected to based on its dependency on claim 1. It is noted that the subject matter of claim 17 could overcome the 35 U.S.C. 112(a) written description rejection. However, based on other rejections the claim is not allowable.
Claim Rejections - 35 USC § 102
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.
Claim 42 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Katsumi (Chem. Pharm. Bull., 2020, 68(7):560-566). Katsumi discloses “a method of treating or preventing bone disease in a subject comprising administering to the subject an effective amount of a bone-targeting conjugate comprising bisphosphonate (BP) conjugated to one or more polypeptides.” (See Katsumi, pg. 562, Section 3.2). Therefore, Claim 42 is anticipated by Katsumi.
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.
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, 5-7, 11-15, 17-18, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Katsumi (Chem. Pharm. Bull., 2020, 68(7):560-566) in view of Lee (Bioconjugate Chem., 2017, 28:1084-1092, as disclosed in IDS from 7/18/2023) as evidenced by Rogers (eLIFE Sciences, 2018).
In regard to claim 1, Katsumi discloses a method for treating bone tumors in a subject comprising administering an effective amount of a bisphosphonate (BP) conjugated to a bone cancer drug or drug carrier. (See Katsumi, pg. 561-562, section 2.2). Katsumi further discloses a conjugated form of trastuzumab (T-DMI) as a treatment for advanced metastatic breast cancer. (See Katsumi, pg. 564, section 5). Katsumi does not disclose a bone-targeting conjugate comprising BP conjugated to an antibody.
Lee discloses a bone-targeting conjugate comprising bisphosphonate (BP) conjugated to an antibody. (Lee, abstract). Lee further teaches the BP conjugated antibody was able to successfully deliver the antibody to treat site-specific disease symptoms at the bone surface. (Lee, abstract).
It would be obvious for a person of ordinary skill to use the BP-antibody construct of Lee along with the disclosure of Katsumi prior to the effective filing date to develop the method of the present claimed invention. Half of patients with metastatic breast cancer will develop bone metastases. (See pg. 1, lines 31-32). Further, current immunotherapy agents for targeting metastatic breast cancer have proven ineffective when administered alone in treating bone metastases. (See pg. 2, lines 14-18). The BP-antibody disclosed by Lee was successful at directing the antibody to bone, so there would be a reasonable expectation of success to conjugate BP to trastuzumab for the same purpose. Therefore, it would have been obvious to a person of ordinary skill in the art prior to the effective filing date to use trastuzumab conjugated to a BP ligand to treat HER2+ bone metastases as claimed in the present invention.
In regards to claim 2 and 3, the limitations of claim 1 are disclosed as discussed above. Katsumi further teaches the use of BP bone targeting ligand for use in treating bone metastases. (See Katsumi, abstract). Further, Katsumi teaches treating bone metastases in metastatic prostate and breast cancer. (See Katsumi, abstract).
In regards to claim 5, the limitations of claim 1 are disclosed as discussed above. As evidenced by Rogers, bisphosphonates contain two negatively-charged phosphonate groups that enable them to bind calcium effectively. (See Rogers, pg. 1, column 2, lines 14-18). Therefore, bisphosphonate ligands binding to bone are only effective as negatively-charged molecules.
In regards to claims 6 and 7, the limitations of claim 1 are disclosed as discussed above. Katsumi further discloses the BPs of alendronate and zoledronate for use as bone-targeting ligands. (See Katsumi, pg. 562, column 1, lines 11-12).
In regards to claim 11-15, the limitations of claim 1 are disclosed as discussed above. Katsumi discloses the use of trastuzumab, an anti-HER2 monoclonal antibody that is an immune checkpoint inhibitor. (See Katsumi, pg. 564, section 5).
In regards to claim 17, the limitations of claim 1 are disclosed as discussed above. Katsumi further discloses alendronate as a popular bone-targeting ligand (Katsumi, pg. 562, column 1, lines 12-15) and trastuzumab as successfully treating advanced metastatic HER2+ breast cancer. (See Katsumi, pg. 564, column 2, section 5, lines 6-8). Therefore, it would have been obvious to use alendronate and trastuzumab in the BP-antibody conjugate to treat HER2+ bone metastases.
In regards to claim 18, the limitations of claim 1 are disclosed as discussed above. Katsumi further discloses trastuzumab is not an anti-MSCF antibody. (See Katsumi. Pg. 564, section 5).
In regards to claim 26, the limitations of claim 1 are disclosed as discussed above. The subject matter of claim 26 is directed towards the results following administration but do not require any additional steps for the method and wherein the administration of the modified bone targeting conjugate as indicated by Katsumi will inevitably results in the endpoints delineated in claim 26.
Claims 19-20 and 22-23 are rejected under 35 U.S.C. 103 as being unpatentable over Katsumi (Chem. Pharm. Bull., 2020, 68(7):560-566) in view of Lee (Bioconjugate Chem., 2017, 28:1084-1092, as disclosed in IDS from 7/18/2023) and in further view of Yu (Bioconjugate Chem., 2018, 29:3522-3526).
In regards to claims 19 and 20, the limitations of claim 1 are obvious over Katsumi in view of Lee as discussed above. However, Katsumi and Lee do not disclose the BP is not conjugated to N-glycan on the Fc region of the antibody. Further, Katsumi and Lee do not disclose the BP being site-specifically conjugated to the antibody using pClick conjugation, NHS-ester chemistry or cysteine chemistry.
Yu discloses pClick as a method for conjugating antibodies to functional molecules without further antibody engineering or UV/chemical treatment. Yu teaches the mechanism of action for this method is proximity-induced reactivity between an adjacent native amino acid and an antibody lysine residue.
It would be obvious for a person of ordinary skill in the art prior to the effective filing date to use the conjugation method of Yu to create the antibody of the present invention. Using a methodology that is specifically designed to conjugate antibodies without interfering with their structure through engineering or chemical modes of action would be ideal for creating the most effective antibody conjugate and is expected to lead to reasonable success. This method would not rely on BP being conjugated to the N-glycan of the Fc region of the antibody. Therefore, a person of ordinary skill in the art prior to the effective filing date would have been motivated to use the conjugation method of Yu to the BP-antibody conjugate of the present claimed invention.
In regards to claim 22, the limitations of claim 1 are disclosed as discussed above. Yu further discloses conjugation of a protein to the CH2-CH3 junction of an IgG antibody. (See Yu, pg. 3523, column 2, lines 11-14).
In regard to claims 23, the limitations of claim 1 are disclosed as discussed above. Yu further discloses the conjugation to an antibody using 4-fluorophenyl carbamate lysine (FPheK). (See Yu, pg. 3523, column 2, lines 18-24).
Claim 28 is rejected under 35 U.S.C. 103 as being unpatentable over Katsumi (Chem. Pharm. Bull., 2020, 68(7):560-566) in view of Lee (Bioconjugate Chem., 2017, 28:1084-1092, as disclosed in IDS from 7/18/2023) and in further view of Richard (Annals of the Brazilian Academy of Sciences, 2016, 88(S1):565-577).
In regard to claim 28, the limitations of claim 1 are disclosed as discussed above. Katsumi and Lee do not disclose the administration of an additional anti-cancer therapy.
Richard teaches the use of administrating both trastuzumab and pertuzumab, two anti-HER2 antibodies to treat HER2+ metastatic breast cancer. (See Richard, pg. 1 abstract).
It would be obvious for a person of ordinary skill in the art prior to the effective filing date to administer another anti-cancer therapy along with the conjugated BP-antibody disclosed in the present invention. Metastatic breast cancer that has spread to bone metastases can be difficult to treat. (See pg. 2, lines 14-16). In treating a difficult cancer, it would be obvious to try multiple different therapies as taught by Richard. Therefore, a person of ordinary skill in the art would be motivated to administer another anti-cancer therapy along side the conjugated BP-antibody of the present claimed invention to treat a difficult cancer.
Conclusion
In summary, claims 1-3, 5-7, 11-15, 17-20, 22-23, 26, 28, and 42 are all rejected.
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/LINDSAY DUNN/Examiner, Art Unit 1644
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642