DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant's election with traverse of the restriction and election of species requirement in the reply filed on 07/07/2026 is acknowledged. The traversal is on the ground(s) that Examiner's citation of prior art does not establish that a special technical feature does not contribute over the known art.
Examiner has considered Applicant’s arguments and finds them persuasive. The restriction requirement and election of species requirement has been withdrawn.
Priority
Examiner acknowledges that, according to the Filing receipt received 04/18/2024, that the instant application 18/554,325 filed 10/06/2023 is a 371 of PCT/CN2022/085706 filed 04/08/2022 which claims foreign priority of PCT/CN2021/086094 filed 04/09/2021. All of the claims have been awarded the effective filing date of 04/09/2021.
Information Disclosure Statement
The Information Disclosure Statements filed on 10/06/2023, 03/12/2025, and 04/23/2026 are in compliance with the provisions of 37 CFR 1.97 and have been considered in full. A signed copy of list of references cited from the IDS is included with this Office Action.
Specification
The disclosure is objected to because of the following informalities:
Page 27: “INCORPORATION BY REFERENC” should read “INCORPORATION BY REFERENCE”;
Paragraphs [0096], [0099], [0102], [0108], [0242], [0255]: “formular” should read “formula”;
Paragraph [0153]: “and the lice” should read “and the like”;
Page 42: the depicted compounds cannot be interpreted due to low resolution.
Appropriate correction is required.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claims 22-24, 33, and 108 are objected to because of the following informalities:
Claims 22-24: the definitions for n2 and n3 (claim 22), n2 and n4 (claim 23), and n2, n5, and n6 (claim 24) should be set forth after they are depicted in the structures of R4 and R6.
Claim 33: R1, R2, and R3 should be subscript.
Claim 108: "a subject in need of" should read "a subject in need thereof".
Appropriate correction is required.
Drawings
The drawings are objected to because Figures 9, 11, 12, 13, 14a, 14b, 14c, 15b, 15c, 16, 17, 23, 24, 26, 28, and 29 are too small and/or low resolution to interpret. The second figures on pages 13/16 and 14/16 of the drawings are not labeled by figure number.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections – Improper Markush Grouping
Claims 1, 4, 8, 15-19, 21-29, 31-32, and 108 are rejected on the judicially-created basis that they contain an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature.
A Markush claim contains an “improper Markush grouping” if: (1) the species of the Markush group do not share a single structural similarity,” or (2) the species do not share a common use. Members of a Markush group share a "single structural similarity” when they belong to the same recognized physical or chemical class or to the same recognized physical or chemical class or to the same art-recognized class. Members of a Markush group share a common use when they are disclosed in the Specification or known in the art to be functionally equivalent (see Federal Register, Vol. 76, No. 27, Wednesday, February 9, 2011, p. 7166, left and middle columns, bridging paragraph).
The members of the improper Markush grouping do not share a substantial feature and/or a common use that flows from the substantial structural feature for the following reasons:
The structure of formula (1) is as below.
PNG
media_image1.png
36
234
media_image1.png
Greyscale
The only common structure shared by each species of formula (1) is L1, which has the structure as below.
PNG
media_image2.png
92
406
media_image2.png
Greyscale
The remainder of the structure is largely functional in nature, wherein M is “a biological macromolecule”, L2 is a “linker”, and D is a “functional molecule” such as a drug. A biological macromolecule ranges from that of a protein to nucleic acids. There is no single structural component or function that must necessarily be shared between biological macromolecules. Moreover, the instant disclosure only sets forth species of the instant invention wherein M is trastuzumab (a monoclonal antibody). A linker is defined by the instant specification in that it “generally refers to a chemical moiety or bond that attaches two or more molecules” (p. 29 of specification). Therefore, a linker can reasonably encompass virtually any structure, or even a bond, between two other moieties. The working examples, however, are limited to PEG groups. See the structures of claim 32, for example. Finally, no single structural similarity is shared by functional molecules, let alone drugs. The term is so broad that it encompasses any molecule that “can play a role in the function of the conjugate” (p. 29 of specification). No structure, shared or otherwise, can be reasonably ascertained from the guidance provided in the specification. Notably, even the functional molecules exemplified in the species of the instant invention differ greatly in their core structure. Below are two species of formula (1) as claimed in claim 32.
PNG
media_image3.png
254
768
media_image3.png
Greyscale
There are no structural similarities shared by the functional molecules of the above species. The upper functional molecule is biotin and is characterized by a fused heterocycle, while the lower functional molecule is MMAE and is characterized by an amino acid chain.
Clearly no ‘‘single structural similarity’’ from which a common function may flow can be seen.
In response to this rejection, Applicant should either amend the claim(s) to recite only individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claim(s) in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature. This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. § 134 and 37 CFR41.31 (a) (1) (emphasis provided).
Claim 33 is rejected on the judicially-created basis that they contain an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature.
A Markush claim contains an “improper Markush grouping” if: (1) the species of the Markush group do not share a single structural similarity,” or (2) the species do not share a common use. Members of a Markush group share a "single structural similarity” when they belong to the same recognized physical or chemical class or to the same recognized physical or chemical class or to the same art-recognized class. Members of a Markush group share a common use when they are disclosed in the Specification or known in the art to be functionally equivalent (see Federal Register, Vol. 76, No. 27, Wednesday, February 9, 2011, p. 7166, left and middle columns, bridging paragraph).
The members of the improper Markush grouping do not share a substantial feature and/or a common use that flows from the substantial structural feature for the following reasons:
The structure of formula (3) is as below.
PNG
media_image4.png
34
238
media_image4.png
Greyscale
The only common structure shared by each species of formula (3) is L1, which has the structure as below.
PNG
media_image5.png
108
248
media_image5.png
Greyscale
The remainder of the structure is largely functional in nature, wherein L2 is a “linker”, and D is a “functional molecule” such as a drug. A linker is defined by the instant specification in that it “generally refers to a chemical moiety or bond that attaches two or more molecules” (p. 29 of specification). Therefore, a linker can reasonably encompass virtually any structure, or even a bond, between two other moieties. The working examples, however, are limited to PEG groups. See the structures pages 48-49 of the specification, for example. Finally, no single structural similarity is shared by functional molecules, let alone drugs. The term is so broad that it encompasses any molecule that “can play a role in the function of the conjugate” (p. 29 of specification). No structure, shared or otherwise, can be reasonably ascertained from the guidance provided in the specification. Notably, even the functional molecules exemplified in the species of the instant invention differ greatly in their core structure. Below are two species of formula (3) as on pages 48-49 of the specification.
PNG
media_image6.png
218
592
media_image6.png
Greyscale
There are no structural similarities shared by the functional molecules of the above species. The lower functional molecule is biotin and is characterized by a fused heterocycle, while the upper functional molecule is MMAE and is characterized by an amino acid chain.
Clearly no ‘‘single structural similarity’’ from which a common function may flow can be seen.
In response to this rejection, Applicant should either amend the claim(s) to recite only individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claim(s) in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature. This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. § 134 and 37 CFR41.31 (a) (1) (emphasis provided).
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 1, 4, 8, 15-19, 21-29, 31-33, 95, 98, 104, 108 and 114 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “H or the isotope thereof”. The limitation “the isotope thereof” lacks antecedent basis. It is unclear which isotope of H is being referred to. Claims 4, 8, 15-19, 21-29, 31-32, and 108 are rejected for requiring and/or not clarifying the limitation at issue.
Claim 1 recites “and a first C, linking R1, and a second C, linking R2, optionally form a ring”. It is unclear what structure is imparted by this limitation. For example, are the first and second C part of the “optionally substituted alkyl, or an optionally substituted aryl” or is the optional ring formed by R1 and R2 an alternative limitation that forms a structure independent of the previous limitations for R1 and R2 set forth in the claim? Claims 4, 8, 15-19, 21-29, 31-32, and 108 are rejected for requiring and/or not clarifying the limitation at issue.
Claim 19 recites “-CO-NH-C≡CH-optionally substituted alkyl”. This structure is not possible because carbon cannot have five bonds (i.e., “C≡CH-optionally substituted alkyl”).
Claim 26 recites “optionally substituted alkyl-N”. However, N has a valence of 3. It is unclear what N is additionally substituted by.
Claim 29 recites “the ring”. This limitation lacks antecedent basis, as it is unclear which ring or ring structure is referred to.
Claim 31 sets forth alternatives for L1. However, all of the structures are monovalent such that the points of attachment between L1 and both M and L2 are unclear. Moreover, at least the last thirteen alternatives contain moieties that appear to be linking groups (e.g., PEG groups). It is unclear whether these structures include an L2 linker despite being set forth as alternatives for L1.
Claim 32 sets forth alternatives for the conjugate of claim 1. However, the structures depicted do not represent the conjugate as a whole in that M is not present. It is therefore unclear whether the structures are a fragment of the conjugate and/or where M is attached to the conjugate.
Claim 33 recites “and a first C, linking R1, and a second C, linking R2, optionally form a ring”. It is unclear what structure is imparted by this limitation. For example, are the first and second C part of the “optionally substituted alkyl, or an optionally substituted aryl” or is the optional ring formed by R1 and R2 an alternative limitation that forms a structure independent of the previous limitations for R1 and R2 set forth in the claim?
Claim 95 recites “optionally substituted alkyl-N”. However, N has a valence of 3. It is unclear what N is additionally substituted by. Claims 98, 104, and 114 do not clarify the limitation at issue and are also rejected.
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.
Claim 108 is 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 treating a disease selected from carcinoma, glomerulonephritis, Goodpasture's syndrome, necrotizing vasculitis, lymphadenitis, peri-arteritis nodosa, systemic lupus erythematosis, rheumatoid arthritis, psoriatic arthritis, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis, polymyositis, anti-phospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis, uveitis, Sjogren's syndrome, Crohn's disease, Reiter's syndrome, ankylosing spondylitis, Lyme arthritis, Guillain-Barre syndrome, Hashimoto's thyroiditis, and cardiomyopathy, does not reasonably provide enablement for treating diseases generally or preventing any disease. 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 invention commensurate in scope with these claims.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, "The Federal Circuit has repeatedly held that "the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation." In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)" (emphasis added). The "make and use the full scope of the invention without undue experimentation" language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: "A lack of enablement for the full scope of a claim, however, is a legitimate rejection." The principle was explicitly affirmed most recently in Liebel-Flarsheim Co. v. Medrad, Inc., 481 F.3d 1371, 82 USPQ2d 1113; Auto. Tech. Int'l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008).
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. Some experimentation is not fatal; the issue is whether the amount of experimentation is "undue"; see In re Vaeck, 20 USPQ2d 1438, 1444.
The treatment of cancer generally cannot possibly be considered enabled.
By way of background, four cases are of particular relevance to the question of enablement of a method of treating cancers broadly or even generally:
In In re Buting, 57 CCPA 777, 418 F.2d 540, 163 USPQ 689, the claim was drawn to "The method of treating a malignant condition selected from the group consisting of leukemias, sarcomas, adenocarcinomas, lymphosarcomas, melanomas, myelomas, and ascitic tumors" using a small genus of compounds. The Court decided that human testing "limited to one compound and two types of cancer" was not "commensurate with the broad scope of utility asserted and claimed".
In Ex parte Jovanovics, 211 USPQ 907 the claims were drawn to "the treatment of certain specified cancers in humans" by the use of a genus of exactly two compounds, the N-formyl or N-desmethyl derivative of leurosine. Applicants submitted "affidavits, publications and data" for one of the compounds, and a dependent claim drawn to the use of that species was allowed. For the other, no data was presented, applicants said only that the other derivative would be expected to be less effective; claims to the genus were refused.
In Ex parte Busse, et al., 1 USPQ2d 1908, claims were drawn to "A therapeutic method for reducing metastasis and neoplastic growth in a mammal" using a single species. The decision notes that such utility "is no longer considered to be "incredible", but that "the utility in question is sufficiently unusual to justify the examiner's requirement for substantiating evidence. Note also that there is also a dependent claim 5 which specified "wherein metastasis and neoplastic growth is adenocarcinoma, squamous cell carcinoma, melanoma, cell small lung or glioma." The decision notes that "even within the specific group recited in claim 5 some of the individual terms used actually encompass a relatively broad class of specific types of cancer, which specific types are known to respond quite differently to various modes of therapy."
In Ex parte Stevens, 16 USPQ2d 1379 a claim to "A method for therapeutic or prophylactic treatment of cancer in mammalian hosts" was refused because there was "no actual evidence of the effectiveness of the claimed composition and process in achieving that utility."
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. Some experimentation is not fatal; the issue is whether the amount of experimentation is "undue"; see In re Vaeck, 20 USPQ2d 1438, 1444.
The analysis is as follows:
1) Breadth of claims.
It is presumed “prevention” of the claimed diseases would require a method of identifying those individuals who will develop the claimed diseases before they exhibit symptoms. There is no evidence of record that would guide the skilled clinician to identify those who have the potential of becoming afflicted.
"Cancer" is not a single disease, or cluster of closely related disorders. There are hundreds of cancers, which have in common only some loss of controlled cell growth. Cancers are highly heterogeneous at both the molecular and clinical level, something seen especially in, for example, the cancers of the breast, brain and salivary glands. They can occur in pretty much every part of the body. To be able to simply stop cancer cells generally from being able to proliferate. Many of these approaches --- and there have been others as well --- have produced anti-cancer drugs. However, despite high hopes for success, and a plausible theory why these should work for cancers generally, none of these approaches have ever produced a drug which come remotely near such a goal.
Specifically, the prior art knows that there never has been a compound capable of treating cancers generally. "The cancer therapy art remains highly unpredictable, and no example exists for efficacy of a single product against tumors generally." (<http://www.uspto.gov/web/offices/pac/dapp/1pecba.htm#7> ENABLEMENT DECISION TREE, Example F, situation 1). A similar statement appears at In re Application of Hozumi et al., 226 USPQ 353: "In spite of the vast expenditure of human and capital resources in recent years, no one drug has been found which is effective in treating all types of cancer. Cancer is not a simple disease, nor is it even a single disease, but a complex of a multitude of different entities, each behaving in a different way". There are compounds that treat a modest range of cancers, but no one has ever been able to figure out how to get a compound to be effective against cancer generally, or even a majority of cancers.
The attempts to find compounds to treat the various cancers arguably constitute the single most massive enterprise in all of pharmacology. This has not resulted in finding any treatment for tumors generally. Indeed, the existence of such a "silver bullet" is contrary to our present understanding in oncology. This is because it is now understood that there is no "master switch" for cancers generally; cancers arise from a bewildering variety of differing mechanisms. Even the most broadly effective antitumor agents are only effective against a small fraction of the vast number of different cancers known. This is true in part because cancers arise from a wide variety of sources, primarily a wide variety of failures of the body's cell growth regulatory mechanisms, but also such external factors such as viruses (an estimated at least 20% are of viral origin e.g. Human papillomavirus, EBV, Hepatitis B and C, HHV-8, HTLV-1 and other retroviruses, and quite possibly Merkel cell polyomavirus, and there is some evidence that CMV is a causative agent in glioblastoma), exposure to chemicals such as tobacco tars, excess alcohol consumption (which causes hepatic cirrhosis, an important cause of HCC), ionizing radiation, and unknown environment factors.
Accordingly, there is substantive "reason for one skilled in the art to question the objective truth of the statement of utility or its scope" (In re Langer, 183 USPQ 288, 297), specifically, the scope of covering cancer generally.
Similarly, In re Novak, 134 USPQ 335, 337-338, says "unless one with ordinary skill in the art would accept those allegations as obviously valid and correct, it is proper for the examiner to ask for evidence which substantiates them." There is no such evidence in this case. Likewise, In re Cortright, 49 USPQ2d 1464, states: "Moreover, we have not been shown that one of ordinary skill would necessarily conclude from the information expressly disclosed by the written description that the active ingredient" does what the specification surmises that it does. That is exactly the case here. Moreover, even if applicants' assertion that cancer in general could be treated with these compounds were plausible --- which it is not ---, that "plausible" would not suffice, as was stated in Rasmusson v. SmithKline Beecham Corp., 75 USPQ2d 1297, 1301: "If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to "inventions" consisting of little more than respectable guesses as to the likelihood of their success."
Different types of cancers affect different organs and have different methods of growth and harm to the body, and different vulnerabilities. The skill thus depends on the particular cancer involved. There are some cancers where the chemotherapy skill level is high and there are multiple successful chemotherapeutic treatments. The mechanism in these situations, however, is not necessarily the same as is alleged for these compounds.
One skilled in the art knows that chemotherapy of brain tumors is especially difficult. This is because 1) the blood-brain barrier, which is often intact in parts or all of a brain tumor, will block out many drugs, as it is the purpose of the blood-brain barrier to protect the brain from alien chemicals, and 2) CNS tumors are characterized by marked heterogeneity, which greatly decreases vulnerability to chemotherapy. As a result, many categories of CNS tumors simply have no chemotherapy available. These include, generally, hemangioblastomas, meningiomas, craniopharyngiomas, acoustic neuromas, pituitary adenomas, optic nerve gliomas, glomus jugulare tumors and chordomas, to name just some. With regard to gliomas, GBM is considered untreatable; no effective agents have emerged for the treatment of GBM, despite 20 years of enrolling patients in clinical trials. It is radiation and surgery which are used for low grade gliomas (e.g. pilocytic astrocytoma and diffuse astrocytomas), as no drug has been found effective. There is no drug treatment established as effective for optic nerve gliomas or gangliogliomas. Indeed, very few gliomas of any type are treated with pharmaceuticals; it is one of the categories of cancer that is the least responsive to drugs.
Lymphomas of the stomach are not commonly treated with anti-cancer agents per se, but instead, surgery or radiation and antibiotic therapy (e.g. amoxicillin, metronidazole, bismuth, and omeprazole) are the primary treatments.
Neuroendocrine tumors of the cervix generally do not respond to chemotherapy.
A number of sarcomas, including alveolar soft part sarcoma (ASPS), retroperitoneal sarcoma, most liposarcomas, and the assorted chondrosarcomas, are generally considered not to respond to chemotherapy; no chemotherapeutic agent has been established as effective.
It is important to note that tumors can need to be treated quite differently even though they are tumors of the same organ. For example, the drugs used most often to treat Wilms tumor, the most common malignant tumor of the kidneys in children, are actinomycin D and vincristine. Such drugs are never used with clear cell renal carcinoma, which is treated, although without much success, with immunotherapy using the cytokines interleukin-2 and interferon-alpha. However, such immunotherapy has never been established as effective in non-clear cell RCC forms such as papillary renal cell carcinoma. Despite strenuous efforts over a period of decades, no chemotherapeutic agent has ever been found effective against this cancer. Cancers of the stomach can be lymphomas, GISTs, carcinoid tumors, carcinomas, or soft tissue sarcomas, and for a single agent to be effective against all or even most of these categories would be contrary to what is known in oncology.
The scope of treating inflammation generally is extraordinarily broad. Inflammation is a process which can take place in virtually any part of the body. There is a vast range of forms that it can take, causes for the problem, and biochemical pathways that mediate the inflammatory reaction. It is one of the most pervasive of all body processes. Inflammation is a very general term which encompasses a huge variety of specific processes.
2) The nature of the invention and predictability in the art.
The instant invention is directed toward a method of treating and/or preventing diseases generally.
With specific reference to cancer, Ex parte Kranz, 19 USPQ2d 1216, 1219 notes the "general unpredictability of the field [of] …anti-cancer treatment." In re Application of Hozumi et al., 226 USPQ 353 notes the "fact that the art of cancer chemotherapy is highly unpredictable". More generally, the invention is directed toward medicine and is therefore physiological in nature. It is well established that "the scope of enablement varies inversely with the degree of unpredictability of the factors involved," and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
3) State of the Prior Art. The claimed compounds are of Formula (1). So far as the examiner is aware these compounds have not been successfully used as broad range anticancer agents, agents for treating autoimmune diseases generally, or agents capable of preventing said diseases.
4) Working Examples. Applicants have provided no working examples which are successfully used as broad range anticancer or autoimmune agents for treatment and/or prevention. Applicants have, however, demonstrated in vitro cytotoxicity and in vivo efficacy of conjugates of the instant invention against SKBR-3, MDA-MB-231, MDA-MB-468, and NCI-N87 cells and/or xenografts (p. 77-78 of specification).
5) Skill of those in the art. The state of the art is that no general procedure is art-recognized for determining which patients generally will suffer from cancers or autoimmune diseases before the fact.
Many, many mechanisms have been proposed over the decades as methods of treating the assorted cancers generally. Cytotoxic agents could be applied directly to the tumor cells, directly killing them. Immunotherapy involves stimulating the patient's immune system to attack cancer cells generally, either by immunization of the patient, in which case the patient's own immune system is trained to recognize tumor cells as targets, or by the administration of therapeutic antibodies as drugs, so the patient's immune system is recruited to destroy tumor cells by the therapeutic antibodies. Another approach would be to increase the amount or activity of the body's tumor suppressor genes, e.g. p53, PTEN, APC and CD95, which can for example activate DNA repair proteins, suppress the Akt/PKB signaling pathway, or initiate apoptosis of cancer cells. The angiogenesis inhibitor strategy was based on cutting off the blood supply that growing tumors need by shutting off the growth of new blood vessels by, for example, suppressing proliferation of endothelial cells or inducing apoptosis of endothelial cells. There is also the cancer stem cell paradigm, which hypothesizes that cancer could be treated generally, either by targeting the cancer stem cells themselves, or by targeting the epithelial-to-mesenchymal transition which supposedly generates the cancer stem cells. Yet another approach is to inhibit one or more of the assorted HSP90 proteins, which will supposedly disrupt the proper folding of signaling proteins that all cancers rely on. Inhibiting telomerase was said to be able to be able to simply stop cancer cells generally from being able to proliferate. Many of these approaches --- and there have been others as well --- have produced anti-cancer drugs. However, despite high hopes for success, and a plausible theory why these should work for cancers generally, none of these approaches have ever produced a drug which come remotely near such a goal.
Accordingly, there is substantive "reason for one skilled in the art to question the objective truth of the statement of utility or its scope" (In re Langer, 183 USPQ 288, 297), specifically, the scope of covering cancer generally. Moreover, even if applicants' assertion that cancer in general could be treated with these compounds were plausible --- which it is not ---, that "plausible" would not suffice, as was stated in Rasmusson v. SmithKline Beecham Corp., 75 USPQ2d 1297, 1301: "If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to "inventions" consisting of little more than respectable guesses as to the likelihood of their success."
6) Scope of the claims. The scope of the claims involves the compounds of the following formula (1):
PNG
media_image1.png
36
234
media_image1.png
Greyscale
and their use as potential treatment or prevention of diseases generally, thus, the scope of claims is very broad.
7) The quantity of experimentation needed. Given the fact that, historically, the development of new cancer drugs has been difficult and time consuming, and especially in view of factors 1 and 4 and 6, the quantity of experimentation needed is expected to be great.
MPEP 2164.01(a) states, "A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)." That conclusion is clearly justified here.
Claims 1, 4, 8, 15-19, 21-29, 31-32, and 108 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 conjugate of formula (1) wherein L1 is a compound of formula (I) wherein R2 is an optionally substituted phenyl; L2 is a PEG linker; D is an auristatin or a pro-apoptotic agent; and M is a monoclonal antibody; wherein a, b, and c are 1, does not reasonably provide enablement for a conjugate of formula (1) generally. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the application coupled with information known in the art without undue experimentation. (United States v. Teletronics Inc., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is needed is not based on a single factor, but rather a conclusion reached by weighing many factors (See Ex parte Forman 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988).
These factors include the following:
1) Amount of guidance provided by applicant. Applicant has demonstrated within the application how to make conjugates such as those in claim 32. However, the instant specification (see pages 69-75) provides no species of formula (1) wherein the substituents are positioned in any location other than wherein L1 is a compound of formula (I) and R2 is optionally substituted phenyl.
Furthermore, the examples in pages 69-75 of the specification are only so broad as to describe a genus wherein a conjugate of formula (1) wherein L1 is a compound of formula (I) wherein R2 is an optionally substituted phenyl; R1', R1, and R3 are hydrogen; L2 is a PEG linker; D is MMAE, Dxd, T785, or biotin; and M is trastuzumab; wherein a, b, and c are 1. No working examples exist of any compounds with differing connectivity from that above, or any other substituents or groups as previously mentioned. As was stated in Morton International Inc. v. Cardinal Chemical Co., 28 USPQ2d 1190 “The specification purports to teach, with over fifty examples, the preparation of the claimed compounds with the required connectivity. However...there is no evidence that such compounds exist...the examples of the '881 patent do not produce the postulated compounds...there is...no evidence that such compounds even exist.” The same circumstance appears to be true here. Hence, Applicants must show that these compounds can be made, or limit the claims accordingly.
2) The nature of the invention and predictability in the art. The invention is directed toward drug conjugates comprising a biological macromolecule conjugated to a sulfonyl fluoride linked to a drug. Regarding predictability in the art, chemistry is generally regarded as unpredictable. See In Re Marzocchi and Horton, 169 USPQ at 367 paragraph 3:
“Most non-chemists would probably be horrified if they were to learn how
many attempted syntheses fail, and how inefficient research chemists are.
The ratio of successful to unsuccessful chemical experiments in a normal
research laboratory is far below unity, and synthetic research chemists, in
the same way as most scientists, spend most of their time working out
what went wrong, and why. Despite the many pitfalls lurking in organic
synthesis, most organic chemistry textbooks and research articles do give
the impression that organic reactions just proceed smoothly and that the
total synthesis of complex natural products, for instance, is maybe a labor-
intensive but otherwise undemanding task. In fact, most syntheses of
structurally complex natural products are the result of several years of
hard work by a team of chemists, with almost every step requiring careful
optimization. The final synthesis usually looks quite different from that
originally planned, because of unexpected difficulties encountered in the initially chosen synthetic sequence. Only the seasoned practitioner who
has experienced for himself the many failures and frustrations which the
development (sometimes even the repetition) of a synthesis usually
implies will be able to appraise such work ......Chemists tend not to publish
negative results, because these are, as opposed to positive results, never
definite (and far too copious)...” Dorwald F. A. Side Reactions in Organic
Synthesis, 2005, Wiley: VCH, Weinheim pg. IX of Preface.
The scope of any compounds, compositions, or pharmaceutically acceptable salts where the variables were not those mentioned above are not adequately enabled or defined. Applicants provide to guidance as how the compounds are made.
3) Number of working examples. The compound core depicted with specific substituents as above represents a narrow subgenus for which Applicant has provided sufficient guidance to make and use; however, this disclosure is not sufficient to allow extrapolation of the limited examples to enable the scope of the compounds instantly claimed. Applicant has provided no working examples of any compounds, compositions, or pharmaceutically acceptable salts where the variables were not those mentioned above.
Within the specification, “specific operative embodiments or examples of the invention must be set forth, Examples and description should be of sufficient scope as to justify the scope of the claims, Markush claims must be provided with support in the disclosure for each member of the Markush group. Where the constitution and formula of a chemical compound is stated only as a probability or speculation, the disclosure is not sufficient to support claims identifying the compound by such composition or formula.” See MPEP 608.01(p).
4) Scope of the claims. The scope of the claims is all of the millions of possible compounds represented by general formula (1).
PNG
media_image1.png
36
234
media_image1.png
Greyscale
The conjugates lack any substantial common core structure, wherein M, L2, and D are all defined by functional properties. M is a biological macromolecule, L2 is a linker, and D is a functional molecule. The genus reads on a virtually endless number of species, as such the claims are incredibly broad.
5) Level of skill in the art. The artisan using Applicant’s invention would be a chemist with a Ph.D. degree and having several years of bench experience.
6) Undue experimentation. MPEP §2164.01 (a) states, "A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)."
The conclusion is clearly justified here that Applicant is not enabled for making these compounds or compositions.
Claim 33 is 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 conjugate of formula (3) wherein L1 is a compound of formula (III) wherein R2 is an optionally substituted phenyl; L2 is a PEG linker; D is an auristatin or a pro-apoptotic agent; wherein a, b, and c are 1, does not reasonably provide enablement for a conjugate of formula (3) generally. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the application coupled with information known in the art without undue experimentation. (United States v. Teletronics Inc., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is needed is not based on a single factor, but rather a conclusion reached by weighing many factors (See Ex parte Forman 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988).
These factors include the following:
1) Amount of guidance provided by applicant. Applicant has demonstrated within the application how to make conjugates such as those in claim 32. However, the instant specification (see pages 69-75) provides no species of formula (1) wherein the substituents are positioned in any location other than wherein L1 is a compound of formula (I) and R2 is optionally substituted phenyl.
Furthermore, the examples in pages 48-49 of the specification are only so broad as to describe a genus wherein a conjugate of formula (1) wherein L1 is a compound of formula (III) wherein R2 is an optionally substituted phenyl; R1', R1, and R3 are hydrogen; L2 is a PEG linker; D is MMAE, Dxd, T785, or biotin; wherein a, b, and c are 1. No working examples exist of any compounds with differing connectivity from that above, or any other substituents or groups as previously mentioned. As was stated in Morton International Inc. v. Cardinal Chemical Co., 28 USPQ2d 1190 “The specification purports to teach, with over fifty examples, the preparation of the claimed compounds with the required connectivity. However...there is no evidence that such compounds exist...the examples of the '881 patent do not produce the postulated compounds...there is...no evidence that such compounds even exist.” The same circumstance appears to be true here. Hence, Applicants must show that these compounds can be made, or limit the claims accordingly.
2) The nature of the invention and predictability in the art. The invention is directed toward drug conjugates comprising a sulfonyl fluoride linked to a drug. Regarding predictability in the art, chemistry is generally regarded as unpredictable. See In Re Marzocchi and Horton, 169 USPQ at 367 paragraph 3:
“Most non-chemists would probably be horrified if they were to learn how
many attempted syntheses fail, and how inefficient research chemists are.
The ratio of successful to unsuccessful chemical experiments in a normal
research laboratory is far below unity, and synthetic research chemists, in
the same way as most scientists, spend most of their time working out
what went wrong, and why. Despite the many pitfalls lurking in organic
synthesis, most organic chemistry textbooks and research articles do give
the impression that organic reactions just proceed smoothly and that the
total synthesis of complex natural products, for instance, is maybe a labor-
intensive but otherwise undemanding task. In fact, most syntheses of
structurally complex natural products are the result of several years of
hard work by a team of chemists, with almost every step requiring careful
optimization. The final synthesis usually looks quite different from that
originally planned, because of unexpected difficulties encountered in the initially chosen synthetic sequence. Only the seasoned practitioner who
has experienced for himself the many failures and frustrations which the
development (sometimes even the repetition) of a synthesis usually
implies will be able to appraise such work ......Chemists tend not to publish
negative results, because these are, as opposed to positive results, never
definite (and far too copious)...” Dorwald F. A. Side Reactions in Organic
Synthesis, 2005, Wiley: VCH, Weinheim pg. IX of Preface.
The scope of any compounds, compositions, or pharmaceutically acceptable salts where the variables were not those mentioned above are not adequately enabled or defined. Applicants provide to guidance as how the compounds are made.
3) Number of working examples. The compound core depicted with specific substituents as above represents a narrow subgenus for which Applicant has provided sufficient guidance to make and use; however, this disclosure is not sufficient to allow extrapolation of the limited examples to enable the scope of the compounds instantly claimed. Applicant has provided no working examples of any compounds, compositions, or pharmaceutically acceptable salts where the variables were not those mentioned above.
Within the specification, “specific operative embodiments or examples of the invention must be set forth, Examples and description should be of sufficient scope as to justify the scope of the claims, Markush claims must be provided with support in the disclosure for each member of the Markush group. Where the constitution and formula of a chemical compound is stated only as a probability or speculation, the disclosure is not sufficient to support claims identifying the compound by such composition or formula.” See MPEP 608.01(p).
4) Scope of the claims. The scope of the claims is all of the millions of possible compounds represented by general formula (3).
PNG
media_image4.png
34
238
media_image4.png
Greyscale
The conjugates lack any substantial common core structure, wherein L2 and D are defined by functional properties: L2 is a linker, and D is a functional molecule. The genus reads on a virtually endless number of species, as such the claims are incredibly broad.
5) Level of skill in the art. The artisan using Applicant’s invention would be a chemist with a Ph.D. degree and having several years of bench experience.
6) Undue experimentation. MPEP §2164.01 (a) states, "A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)."
The conclusion is clearly justified here that Applicant is not enabled for making these compounds or compositions.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 4, 8, and 15-17 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhang et al. (J. Label Compd. Radiopharm.; 2018; IDS filed 04/23/2026).
Zhang et al. discloses conjugated ethenesulfonyl fluoride compounds in Table 1 and Table 2 (p. 853-854). Zhang et al. discloses conjugation of ethenesulfonyl fluoride with albumin (BSA) and insulin (Table 2; p. 854, col. 2). Per the structure depicted in Table 1, these conjugates are within the scope of the claims wherein R1’ and R1-R3 are hydrogen, R is -F, L2 is an uncharged linker (-NH-), and M is a protein linked to L1.
Claim(s) 33 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zheng et al. (PNAS; 2019; IDS filed 04/23/2026). Examiner has attached a copy of the Supporting Information referred to in the following rejection.
Zheng et al. discloses the following compounds (Table S1, S-26 and S-27).
PNG
media_image7.png
73
469
media_image7.png
Greyscale
The compounds are within the scope of claim 33 wherein R1 and R3 are -H, R2 is optionally substituted aryl, and L2 is a linker linked to R2.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MADELINE E BRAUN whose telephone number is (703)756-4533. The examiner can normally be reached M-F 8:30am-5:00pm ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Murray can be reached at (571) 272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/MADELINE E BRAUN/Examiner, Art Unit 1624 08/07/2026
Prosecution Insights