Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION.
Priority
Acknowledgement is made of applicant’s claim for foreign priority based on an application filed on November 26, 2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement (IDS)
The information disclosure statements (IDS) submitted have been considered by the examiner.
Status of applications, Amendments, and/or Claims
The Response filed 28 July 2026 has been entered in full. Claims 2-4 have been canceled without prejudice or disclaimer and claims 1,5 are currently amended. Therefore, claims 1, 5-13 are the subject of this Office Action.
The rejection of claims 1-10, 12-13 rejected on the ground of 35 U.S.C 102 (a)(1) as anticipated as set forth at pp. 2-5 are withdrawn in view of Applicant’s amendments or cancellation of the claims.
The rejection of claim 11 on the ground of 35 U.S.C 103 for obviousness as set forth at pp. 5-8 is withdrawn in view of Applicant’s cancellation of the claims.
New Claim Rejections - 35 USC § 112
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.
Claim 1 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 the terms: “a cell”, “contacting” the cell with an antibody ENO-1, which specifically binds to extracellular or membrane-associated Eno-1 of the cells. However, the use of “a” and “the” are interpreted as a specific type of the cell. Therefore, it is unclear the type of cell that is being claimed in the invention. In addition, it is unclear how the contact between the cell with the antibody would be made”. Thus, claim 1 is indefinite.
Claim 5 recites “human disease” arising from aberrant or expression of “an” alpha-enolase (ENO-1) by regulating the cell”. However, it is unclear which human disease, and which ENO-1 are being claimed. In addition, the claim recites “a subject in need”. However, it is unclear who the subject in need is claimed. Therefore, claim 5 is indefinite.
Claim 9 recites “he administering step is provided with a dosing regimen comprising one or more dosing cycles of the ENO-1 anti “, “a fixed dose of about 10-3000mg every 2 to 4 weeks.” However, the use of the terms “about” and “one or more” is indefinite. Also, it is uncertain how a fixed dose can range between 10-3000mg. Therefore, claim 9 is indefinite.
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.
Claims 1, 5-13 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.
The following quotation from section 2163 of the Manual of Patent Examination
Procedure is a brief discussion of what is required in a specification to satisfy the 35 U.S.C. 112 written description requirements for a generic claim covering several distinct inventions:
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice... reduction to drawings...or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus... See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
Thus, when a claim covers a genus of inventions, the specification must provide written description support for the entire scope of the genus. Support for a genus is generally found where the applicant has provided a number of examples sufficient so that one in the art would
recognize from the specification the scope of what is being claimed.
Claims 1,5 recite an anti-ENO-1 antibody comprising a heavy-chain variable domain having three complementary regions including HCDR1 having the amino acid sequence set forth in SEQ ID NO: 1 or having the amino acid sequence set forth in SEQ ID NO: 7, wherein X is any amino acid but cysteine, HCDR2 having the amino acid sequence set forth in SEQ ID NO: 2, and HCDR3 having the amino acid sequence set forth in SEQ ID NO: 3; and a light-chain variable domain having three complementary regions including LCDR1 having the amino acid sequence set forth in SEQ ID NO: 4,LCDR2 having the amino acid sequence set forth in SEQ ID NO: 5, and LCDR3 having the amino acid sequence set forth in SEQ ID NO: 6.
Regarding the claims to an anti-alpha-enolase (ENO-1) specifically binding to extracellular or membrane-associated ENO-1 of the cell, whereby requires a genus of antibodies which has one of the recited sequences as HCDR1 having the amino acid sequence set forth in SEQ ID NO: 7, wherein X is any amino acid but cysteine specifically binding to extracellular or membrane-associated ENO-1. Claims 1,5 discloses 6 CDR sequences and an alternative HCDR of SEQ ID NO: 7, wherein X is any amino acid but cysteine. Thus, the claims are interpreted to encompass at least 19 additional variant antibodies, because X is any other amino acid residue from 20 amino acid residues except the amino acid, cysteine. Thus, under the broadest reasonable interpretation, claims 1,5 encompass a genus of antibodies to bind ENO-1. Further, the full genus of antibodies must be able to bind to ENO-1.
However, it is apparent that the specification does not teach the full breath of genus, wherein an antibody binding to ENO-1 or an antigen binding fragment thereof, and has not recited the 19 possible CDR sequence of claim 1,5 or fully disclaimed since the whole HCDR1 sequence of SEQ ID NO: 7 remains unknown. Therefore, claims 1,5 are rejected for lack of adequate written description support.
The full genus of antibodies binding to ENO-1 is unknown and/or not readily reproducible by the artesian. When determining the representative examples and the art, it is important to consider whether there is evidence of a singular shared structural feature which imparts the defining property of the claimed genus, and which would necessarily be present in every species of the claimed genus.
Thus, one of skill in the art would not readily recognize the use of one genus of antibodies, which is a HCDR1 sequence of SEQ ID NO: 7, wherein X is any amino acid residue but cysteine as claimed by the applicant if there is lack of written description of functionality, which is the ability of the genus to bind ENO-1. Claim 1, 5-13 are rejected for lack of adequate written description support.
It is apparent that there is no support of the claimed genus in the specification. The specifications do not disclose the variants of the antibody of the invention, or an antigen binding fragment thereof. It is not clear what underlies the suggested substitutions as the alternative embodiments were not reduced to practice to demonstrate that they maintain binding to the target; no guidance it provided to the skilled artisan as to which substitutions to choose to incorporate. Further, the potential alternative residue substitutions are not claimed; rather, the claim encompasses numerous potential substitutions beyond those described in the specifications. When determining the representative examples and the art, it is important to consider whether there is evidence of a singular shared structural feature which imparts the defining property of the claimed genus, and which would necessarily be present in every species of the claimed genus.
Therefore, claims 1, 5 and dependent claims 6-13 are rejected for lack of adequate written description support.
Regarding the state of the art; it is known in the art that the antigen binding domain of an antibody requires the 6 complementarity determining regions (CDR) of the heavy and light chains, whereby the 3 CDRs of the heavy chain and the 3 CDRs of the light chain are structurally inter-dependent in forming the unique binding pocket of the antibody paratope region; and thus, the CDRs constitute critical aspects of the antibody paratope and ultimately impart the paratope-epitope binding functionality with regard to specificity and affinity (for review see MacCallum et al., 1996). However, the structure-to-function correlation continues to be highly unpredictable. For example, Chen et al., (1992) teaches that a single amino acid substitution in the VH CDR2 of PC-specific T15 antibody could increase, decrease or ablate binding the target antigen (abstract, Fig. 3), and this occurred in an unpredictable manner based on which residue was mutated. Similarly, a single point mutation in the heavy chain CDR3 region of the high affinity anti-VEGF antibody G6.31, could in some cases enhance, or otherwise completely ablate binding to the target antigen, and this also occurred in an unpredictable manner (Koenig et al., PNAS, 2017). That is, only screening each mutation individually provided insight as to the resulting changes in functionality. In some cases, this extends even beyond the CDRs. Within the framework regions, Koenig et al. (PNAS, 2017) teaches that various amino acid point mutations can increase or decrease binding or neutralization capacity. Some amino acid residues are more tolerant to substitution, while other “conserved” residues are less tolerant, such that a single amino acid substitution may defunctionalize the antibody (pg. E487, Figure 1).
Further, it is known that the heavy chain CDR2 and CDR3 regions contain most of the residues that have a major contribution to the binding free energy of the antigen binding domain (Dondelinger et al., 2018; page 8, column 1, paragraph 2 – column 2, paragraph 1). Regarding single domain antibodies (sdAbs), which comprise only a VHH heavy chain, comprising the 3 heavy chain CDRs, Sheriff et al., (1998) teaches that while the usual conception is that an antibody (or receptor) envelops its ligand, with sdAbs derived from camels, the antibody inserts a part of its binding surface deeply into a pocket on the surface of the ligand; and that about 70% of the total surface area buried in this interaction is contributed by CDR3 (page. 735, column 2, paragraph 2 – column 3, paragraph 1). Thus, the CDR3 of sdAbs is of considerable importance to the functionality of the sdAb with regard to specificity and affinity.
Thus, the hyper-variable regions, comprising the complementary set of CDRs, are well established in the art as the portion of the binding regions which impart the specificity of the antibody; and yet, there is no way to look at an amino acid sequence and envision, a priori, whether the combination of CDRs will bind a particular epitope, even when the CDRs are highly related, without teachings of the basic shared amino acid residues that are sufficient to impart functional binding across all variants. Further, even when provided with several related antibodies that bind the desired target, this does not represent the potentially unknowable breadth of all possible amino acid sequences which will result in the desired binding properties. This is exemplified by the Court decision in Abbvie (Abbvie v Janssen 759 F.3d 1285 (Fed. Cir. 2014)), where Abbvie developed over 200 antibodies that shared 99.5% identity in the variable regions (pg. 7) and which bound the target, but in no way allowed one to envisage the unique structure of Centocor’s antibodies which bound the same target but shared only 50% sequence similarity (see table on pg. 11). Thus, when claiming a genus of antibodies, or antigen binding polypeptides, based on their binding to a common target, the representative examples must cover the full scope of structural variabilities which encompass all species variants that would bind the target.
Section 2163(II)(A)(3)(a)(ii) of the MPEP states that the written description for a claimed genus may be satisfied through either a) a representative number of species, or b) disclosed correlation between function and structure. Here the applicants do not provide any variants of the claimed embodiments, in which alternative mutations were made, which were reduced to practice; nor do they identify the shared structural properties of the variants, such as the CDR residues or humanized framework regions, that would define the genus beyond the desired functionality.
Thus, one of skill in the art would not readily recognize the use of one genus of antibodies claimed by the applicant if there is lack of written description of the ability of the genus to bind ENO-1.
The written description requirement is not fulfilled by the applicant. The written description requirement is not fulfilled by the applicant.
“The purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04. Otherwise, the “claims merely recite a description of the problem to be solved while claiming all solutions to it and … cover any compound later actually invented and determined to fall within the claim’s functional boundaries- leaving it to the pharmaceutical industry to complete an unfinished invention.” Ariad Pharmaceuticals, Inc. v. Eli Lilly and Co., 598 F.3d 1336, 1353 (Fed. Cir. 2010).
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
Therefore, neither the art nor the specification provide the full antibodies genus that can be bound to ENO-1 as claimed by the invention.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the Applicant must convey with reasonable clarity to those skilled in the art, that as of the filing date sought, he or she was in possession of the invention. The invention is for purposes of the “written description” inquiry, whatever is now claimed. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
In view of this uncertainty and the lack of a representative number of examples of the claimed genus, claims 1, 5-13 are rejected for lack of adequate written description support.
In order to comply with the written description requirement, the applicant must fully disclosure the full genus of antibodies to binding ENO-1 by the applicant’s invention in the specifications.
Claims 10-13 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 claims contain 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.
The instant claims are drawn to a method of treating diseases comprising cancers, immune diseases, or fibrotic disease; wherein the cancers comprise gastrointestinal cancer, including colon cancer, colorectal cancer, esophagus cancer, gastric cancer, hepatocellular cancer, liver cancer and pancreatic cancer, lymphoproliferative disorders, including lymphoma, lung cancer, including non-small cell lung cancer, including adenocarcinoma of the lung, squamous carcinoma of the lung, and small-cell lung cancer, blood cancer, including leukemia, bladder cancer, blastoma, brain cancer, breast cancer, cancer of the peritoneum, cervical cancer, endometrial or uterine carcinoma, glioblastoma, glioma, head and neck cancer and kidney cancer; wherein the immune diseases comprise multiple sclerosis, systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, atherosclerosis, macrophage activation syndrome, psoriasis, atopic dermatitis, or inflammatory bowel diseases; wherein the fibrotic diseases comprises idiopathic pulmonary fibrosis, pulmonary hypertension, emphysema, nonalcoholic steatohepatitis, pancreatic fibrosis, renal fibrosis, intestinal fibrosis, cardiac fibrosis, myelofibrosis, arthrofibrosis, systemic sclerosis, interstitial lung diseases, non-specific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP), endomyocardial fibrosis, mediastinal fibrosis, retroperitoneal fibrosis, progressive massive fibrosis (a complication of coal workers' pneumoconiosis), nephrogenic systemic fibrosis, Crohn's disease, old myocardial infarction, scleroderma/systemic sclerosis, neurofibromatosis, Hermansky-Pudlak syndrome, diabetic nephropathy, hypertrophic cardiomyopathy (HCM), hypertension- related nephropathy, focal segmental glomerulosclerosis (FSGS), radiation-induced fibrosis, uterine leiomyomas (fibroids), alcoholic liver disease, hepatic steatosis, hepatic fibrosis, hepatic cirrhosis, hepatitis C virus (HCV) infection, chronic organ transplant rejection, fibrotic conditions of the skin, keloid scarring, Dupuytren contracture, Ehlers-Danlos syndrome, epidermolysis bullosa dystrophica, oral submucous fibrosis, and fibro- proliferative disorders.
Claims 11-13 encompass several forms/types of cancers, immune and fibrotic diseases. However, the specification does not teach the treatment of all types and forms of cancers, immune and fibrotic diseases said to be treatable by the applicant’s method. It is noted that the specifications teach that ENO-1 mAb reduced lactated production in human myeloma cell lines, indicating inhibition of glycolysis. See Figure 3; para [0020]. The antibody also reduced lactate production and migration of prostate cancer cell line PC-3 in a dose dependent manner. See Figure 5; and reduced lactate production in primary endothelial cells and lung fibroblasts, indication inhibition of glycolysis, See Figure 6; and reduced lactate production in the lungs and bronchoalveolar lavage fluid in a murine model of bleomycin-induced pulmonary fibrosis. See Figure 7; para [0024]. However, there is uncertainty regarding the use of the method for the type and form of cancers, immune and fibrotic diseases mentioned above. Thus, one of ordinary skill in the art would not readily recognize the use of the method to treat all types and forms of cancers, immune and fibrotic diseases claimed by the applicant if there is a lack of written description of method and use of the genus (types/forms of cancers, immune and fibrotic diseases) in the claims. Therefore, the written description requirement is not fulfilled by the applicant.
From the Court decision, AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014) with regard to the written description requirement, “analogizing the genus to a plot of land, if the disclosed species only abide in a corner of the genus, one has not described the genus sufficiently to show that the inventor invented, or had possession of, the genus. He only described a portion of it.” Indeed, that is the case here too. The decision continues, explaining:
With the written description of a genus, however, merely drawing a fence around a perceived genus is not a description of the genus. One needs to show that one has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus. See Ariad, 598 F.3d at 1353 (The written description requirement guards against claims that “merely recite a description of the problem to be solved while claiming all solutions to it and . . . cover any compound later actually invented and determined to fall within the claim’s functional boundaries.”). Id. p. 23.
In order to comply with the written description requirement, the applicant must fully disclosure all types and forms of cancer, immune and fibrotic diseases claimed to be treatable by the applicant’s invention regarding the method for all forms/types of claimed diseases in specifications.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus. Thus, the method recited in claims 11-13 must be able to treat any types and forms of cancer, immune and fibrotic diseases recited in claims 11-13.
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: ...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc., 107 F.3d 1565, 1572, 41 USPQ2dl961,1966 (1997); In re Gosteli, 872 F.2dl008,1012,10 USPQ2dl614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d.
Therefore, neither the art nor the specification provides a representative number of cancers, immune and fibrotic diseases and that can be treated by the claim invention.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the Applicant must convey with reasonable clarity to those skilled in the art, that as of the filing date sought, he or she was in possession of the invention. The invention is for purposes of the “written description” inquiry, whatever is now claimed. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Therefore, for all these reasons the specification lacks adequate written description, and one of ordinary skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
The specification does not clarify or describe the treatment to treat all types and forms of cancers, immune and fibrotic diseases listed in claims 11-13 used to treat the types and forms of cancer in the invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
"Applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.).
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for treating all types and forms of cancer, immune and fibrotic diseases claimed in the invention. In addition, the claimed invention is a method for treating a human subject and there are no teachings regarding this limitation because the specification only teaches human culture cells and murine model, which is not the same as treating any of those claimed diseases in a human patient. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Therefore, for all these reasons the specification lacks adequate written description, and one of ordinary skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
New Claim Rejections - 35 USC § 102
Necessitated by amendment
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 5-13 rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tsai et al. (US 9382331-B2; hereafter Tsai; PTO-892).
As claims 1, 5, 10-13, Tsai teaches “methods for generation and use of antibodies that bind specifically to the human alpha-enolase protein (ENO1)”. Tsai teaches that “specifically, activation of plasminogen can result in extracellular matrix degradations, which in turn can lead to increased metastasis of cancer cells and infiltration of immune cells. In other words, ENO1 expression on cancer cell surfaces as a plasminogen receptor can increase invasion activities of the cancer cells. Therefore, ENO1 is a potential target for cancer therapy”. See claim 1; column 1; lines 64-67; column 2; lines 1-3.
Tsai teaches that “the antibody of the invention can be used to treat a human ENO1 protein-related disease or disorder. A human ENO1 protein related disease or disorder may be any condition arising from aberrant activation or expression of human ENO1 protein. Examples of such diseases include where human ENO1 protein aberrantly interacts with its ligands, thereby altering cell-adhesion or cell signaling properties. This alteration in cell adhesion or cell signaling properties can result in neoplastic diseases or some immune diseases. Column 4; lines 37-45.
Tsai teaches the invention, a targeted binding agent is an antibody that can bind to human ENO1 to inhibit extracellular matrix degradation, thereby inhibiting cancer cell dissociation from the extracellular matrix. For example, an antibody of the invention can inhibit greater than 40%, 50%, or 60% of plasminogen mediated dissociation of CL1-5 cells from collagen or fibronectin at antibody concentrations as low as 50 microgram/ml or less. Column 2; lines 46-60.
Tsai teaches a targeted binding agent (i.e. an antibody) may comprise a heavy chain amino acid sequence having a complementarity determining region (CDR) comprising one of the CDR sequences included in sequence 1. See claims 1-9.
Tsai teaches a targeted binding agent (i.e. an antibody) may comprise a light chain amino acid sequence having a complementarity determining region (CDR) comprising one of the CDR sequences included in sequence 2. See claims 1-9.
Tsai teaches SEQ ID NOs: 1-2. The HCDs of SEQ ID NOs: 1-3 are 100% identical to the CDRs in SEQ ID NO: 1 of Tsai et al. (US 9382331-B2; PTO-892) and the LCDRs of SEQ ID NO: 4-6 are 100% identical to the CDRs in SEQ ID NO: 2 of (US 9382331-B2; PTO-892). See claims 1- 9. Figures below.
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Tsai teaches a targeted binding agent is an antibody that can bind to human ENO1 to inhibit extracellular matrix degradation, thereby inhibiting cancer cell dissociation from the extracellular matrix. For example, an antibody of the invention can inhibit greater than 40%, 50%, or 60% of plasminogen. See column 2; lines 53-59.
Tsai teaches mediated dissociation of CL1-5 cells from collagen or fibronectin at antibody concentrations as low as 50 microgram/ml or less. See column 2; lines 46-60.
Tsai teaches that the administration of EN10 mAb with complement twice per week has an efficacy similar to that treated with a same dose of commercial drug Erbitux™ in the CL1-5 xenograft mouse model. See Figure 16.
Tsai teaches methods for inhibiting ENO1-induced cell dissociation from extracellular matrix of cancers in a subject. These methods may include selecting a subject (e.g., a human or an animal) in need of treatment for ENO1-induced cell dissociation, and administering to said subject a therapeutically effective dose of an antibody, wherein said antibody specifically binds to ENO1. The antibody may be a humanized or fully human monoclonal antibody. See column 4; lines 29-36.
Tsai teaches the methods for treating diseases or conditions associated with the expression of ENO1 in a patient. The methods may include administering to a patient an effective amount of an anti-ENO1 antibody. The anti-ENO1 antibody can be administered alone, or can be administered in combination with additional antibodies or chemotherapeutic drug or radiation therapy. For example, a monoclonal, oligoclonal or polyclonal mixture of ENO1 antibody that block cell dissociation can be administered in combination with a drug shown to inhibit tumor cell proliferation directly. The method can be performed in vivo, and the patient is preferably a human patient. The method concerns the treatment of an ENO1-related disease or disorder including, but not limited to, neoplastic diseases, such as lung, breast, pancreas, liver, colorectal, prostate cancers and or solid tumors. See abstract; column 4; lines 46-49.
Tsai teaches compositions comprising a targeted binding agent, which may include an antibody or a functional fragment thereof, and a pharmaceutically acceptable carrier. See column 4; lines 25-29.
Regarding the limitations of claims 6-8, which are dependent of the method of claim 5, wherein the administering step is by oral, parenteral, buccal, vaginal, rectal, inhalation, insufflation, sublingual, intramuscular, subcutaneous, topical, intranasal, intraperitoneal, intrathoracic, intravenous, epidural, intrathecal, or intracerebroventricular route, or by injection into joint; wherein the administering step is by intravenous bolus injection or intravenous infusion over 30, 60 or 120 minutes,; wherein the administering step is by subcutaneous bolus injection; wherein the administering step is by subcutaneous bolus injection.”, the claim teaches all structural features from the claim, so it is presumed to be capable of the claimed intended use because if “a method of treating human disease arising from aberrant activation or expression of an alpha-enolase (ENO-1) by regulating glycolysis in a cell, comprising administering to a subject in need a therapeutically effective amount of anti-ENO-1 antibody targeting extracellular or membrane-associated ENO-1”, then any selected administering step of claim 6 can be used to treat a subject using the method of claim 5. See MPEP 2112.01: "Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Therefore, the prima facie case can be rebutted by evidence showing that the prior art products do not necessarily possess the characteristics of the claimed product. In re Best, 562 F.2d at 1255, 195 USPQ at 433." See also MPEP 2111.02: "To satisfy an intended use limitation which is limiting, a prior art structure which is capable of performing the intended use as recited in the preamble meets the claim. See, e.g., In re Schreiber, 128 F.3d 1473, 1477, 44 USPQ2d 1429, 1431 (Fed. Cir. 1997)"
Therefore, the inventions of claims 1, 5-13 are anticipated by Tsai.
Applicants’ arguments directed to the rejections will be addressed below. See response to arguments.
Response to Amendments
Applicants’ arguments as they pertain to the rejections have been fully considered but are not persuasive for the following reasons.
Applicant argues at pg. 6-7, 9 of the Response (filed 28 July 2026) that “Amended claims 1 and 5 each require an anti-ENO-1 antibody comprising a heavy-chain variable domain with "HCDR1 having the amino acid sequence set forth in SEQ ID NO: 1 or having the amino acid sequence set forth in SEQ ID NO: 7, wherein X is any amino acid but cysteine," "HCDR2 having the amino acid sequence set forth in SEQ ID NO: 2," and "HCDR3 having the amino acid sequence set forth in SEQ ID NO: 3," and a light-chain variable domain with "LCDR1 having the amino acid sequence set forth in SEQ ID NO: 4," "LCDR2 having the-6-amino acid sequence set forth in SEQ ID NO: 5," and "LCDR3 having the amino acid sequence set forth in SEQ ID NO: 6." (Amended claims 1 and 5). Because Tsai does not disclose the recited antibody structure, Tsai cannot anticipate amended claims 1 or 5.
In response to Applicant’s arguments, the examiner searched for the six CDRs sequences of amended claims 1, 5. The six CDR sequences claimed in the present invention have 100% identity with the CDR sequences in the SEQ ID NOs: 1-2 of Tsai et al. (US 9382331-B2). See alignment Figures above; 102 rejections. Furthermore, Tsai teaches that “A further aspect of the invention is an antibody molecule comprising a VH domain that has at least about 60, 70, 80, 85, 90, 95, 98 or about 99% amino acid sequence identity with a VH domain of any of antibodies listed in sequences 1, the appended sequence listing or described herein, or with an HCDR (e.g., HCDR1, HCDR2, or HCDR3) shown in sequence 1. The antibody molecule may optionally also comprise a VL domain that has at least 60, 70, 80, 85, 90, 95, 98 or 99% amino acid sequence identity with a VL domain of any of the antibodies shown in sequences 2, the appended sequence listing or described herein, or with an LCDR (e.g., LCDR1, LCDR2, or LCDR3) shown in sequence 2. Algorithms that can be used to calculate % identity of two amino acid sequences comprise e.g. BLAST, FASTA, or the Smith-Waterman algorithm”. “A further aspect of the present invention relates to a targeted binding agent (i.e. an antibody) including those for which amino acid sequences that binds to the epitope peptide comprising amino acid sequence that has at least about 60, 70, 80, 85, 90, or about 92% amino acid sequence identity listed in sequences 9 or 10 on human ENO1 protein and can be used to treat an human ENO1 protein disease or disorder. A human ENO1 protein-related disease or disorder can be any condition arising due to the aberrant activation or expression of human ENO1 protein. In one example, the human ENO1 protein-related disease is a neoplastic disease such as non-small cell lung cancer, hepatocellular (liver) carcinoma, gastric (stomach) cancer, breast cancer, pancreatic duct adenocarcinoma.
Therefore, Tsai does disclose the six CDRs of amended claims 1-5, and amino acid sequences that bind to the epitope peptide comprising amino acid sequence that has at least about 60, 70, 80, 85, 90, or about 92% amino acid sequence identity listed in sequences 9 or 10 on human ENO1 protein and can be used to treat an human ENO1 protein disease or disorder.
Applicant argues at pg. 7-8 of the Response (filed 28 July 2026) that “Tsai does not disclose regulation of glycolysis through the claimed extracellular or membrane-associated ENO-1 targeting. Claim 1 is directed to "[a] method for regulating glycolysis in a cell" and requires "contacting the cell with an anti-alpha-enolase (ENO-1) antibody which specifically binds to extracellular or membrane-associated ENO-1 of the cell." Claim 5 requires treating disease "by regulating glycolysis in a cell" through administration of "an anti-ENO-1 antibody targeting extracellular or membrane-associated ENO-1. Tsai states that ENO1 was first identified as a glycolytic enzyme in the cytosol and separately states that ENO1 can be expressed on cell surfaces as a plasminogen receptor. (Tsai, para. [0007], p. 3.) Tsai then defines its therapeutic mechanism in terms of the latter function: "The methods use an antagonist that can bind to ENO1 to inhibit its function as a receptor for plasminogen. By such inhibition, plasminogen activation is inhibited," thereby preventing or reducing downstream reactions involving plasmin. (Tsai, para. [0069], p. 14.) Tsai likewise describes inhibition of monocyte invasion and migration through compromise of ENO1 plasminogen-receptor and UPAS activity. (Tsai, paras. [0033]-[0036], pp. 9-10.) " These disclosures do not state that an antibody bound to extracellular or membrane- associated ENO1 regulates glycolysis in the contacted cell or treats disease by that mechanism.
In response to Applicant’s arguments, Tsai teaches that “Alpha-enolase (enolase-1, ENO1) is a multiple functional protein, which was first found as a key enzyme of the glycolysis pathways. Under normal conditions, ENO1 is expressed in the cytosol. However, ENO1 is also found to express on the cell surfaces of many cancer cells as a plasminogen receptor and on activated hematopoietic cells, such as neutrophils, lymphocytes and monocytes. It is known that the up-regulation of plasminogen receptor proteins can induce a cascade response of the urokinase plasminogen activation system (uPAS). Also, the urokinase plasminogen activator system (uPAS) consists of the urokinase plasminogen activator (uPA), its cognate receptor (uPAR) and two specific inhibitors, the plasminogen activator inhibitor 1 (PAI-1) and plasminogen activator inhibitor 2 (PAI-2). Urokinase plasminogen activator converts plasminogen proenzyme into an active serine protease, plasmin. Plasmin is involved in a number of tissue remodeling processes, such as basement membrane (BM) and extracellular matrix (ECM) remodeling, which is required in tumor progression and metastasis. In addition, it has been shown that the uPAS may be involved in the neoplastic evolution, affecting tumor angiogenesis, malignant cell proliferation, adhesion and migration, intra-vascularization, and growth at the metastatic site. Finally, “the antibody of the invention can be used to treat a human ENO1 protein-related disease or disorder. A human ENO1 protein related disease or disorder may be any condition arising from aberrant activation or expression of human ENO1 protein. Examples of such diseases include where human ENO1 protein aberrantly interacts with its ligands, thereby altering cell-adhesion or cell signaling properties. This alteration in cell adhesion or cell signaling properties can result in neoplastic diseases or some immune diseases. Tsai does not have restricted the use of the antibody only for cancers, since the antibody of the invention can be used to treat a human ENO1 protein-related disease or disorder. A human ENO1 protein related disease or disorder may be any condition arising from aberrant activation or expression of human ENO1 protein.
Therefore, the claimed invention is anticipated by Tsai because the use of the antibody comprising the CDRs of SEQ ID NOS:1-6 binds ENO-1 protein, which is a protein-related disease or disorder as taught by Tsai. The examiner must remind the applicant that antibodies “contact” the cell via chemical interactions between antibody and cell ligands. Thus, the claimed “contact” is mediated via chemical interactions and Tsai does teach that “the antibody of the invention can be used to treat a human ENO1 protein-related disease or disorder. A human ENO1 protein related disease or disorder may be any condition arising from aberrant activation or expression of human ENO1 protein. Examples of such diseases include where human ENO-1 protein aberrantly interacts with its ligands, thereby altering cell-adhesion or cell signaling properties. This alteration in cell adhesion or cell signaling properties can result in neoplastic diseases or some immune diseases. Therefore, Tsai teaches all the claim limitations.
Applicant argues at pg. 8-9 of the Response (filed 28 July 2026) that “Tsai discloses intravenous injection and generic infusions, but does not disclose an intravenous bolus or a 30-, 60-, or 120-minute infusion. (Tsai, para. [0025], pp. 7-8.) The Office Action cites Tsai paragraphs [0029]-[0030] for claim 7, but those paragraphs concern determining an effective dose and do not disclose the recited administration duration. (Office Action, p. 5; Tsai, paras. [0029]-[0030], pp. 8-9.) Claim 8 requires "subcutaneous bolus injection." (Claim 8.) Tsai refers generally to subcutaneous injection but does not expressly identify the administration as a bolus. (Tsai, para. [0025], pp. 7-8.). Claim 9 requires "one or more dosing cycles of the ENO-1 antibody at a fixed dose of about 10-3000 mg every 2 to 4 weeks." (Claim 9.) Tsai paragraphs [0029]-[0030] describe determining an effective dose and increasing doses in a test series, but they do not disclose the-8-claimed fixed dose, the claimed 10-3000 mg range, the claimed dosing-cycle structure, or the claimed two-to-four-week interval. (Tsai, paras. [0029]-[0030], pp. 8-9.) Accordingly, Tsai does not anticipate claim 9 for this additional reason”.
In response to Applicant’s arguments, the applicant should recognize that one skilled in the art at the effective filling date would have known how to adjust the doses regimen, and suitable forms of administration of the antibody in a subject for treating a disease related to ENO-1 using the antibodies of Tsai. Because one skilled in the art would know that any protocol used to treat a human patient (or any subject in need) depends on several factors, including patient’s age and general health conditions, and disease to be treated. However, the specifications do not teach that the method can treat all types/forms of cancers, immune diseases, and fibrotic diseases claimed in the present invention, especially in humans. It is apparent that the applicant was not fully in possession of the claimed invention at the time of the filed application. Even if one argues that Tsai does not disclaim the same exact protocol treatment claimed in the present invention, the antibody taught by Tsai has the same CDRs sequences of the antibody claimed in the present invention. Thus, one skilled in the art would eventually find out the dose regimens claimed in the invention by using the antibody of Tsai, especially because the administering step is provided with a dosing regimen comprising one or more dosing cycles of the ENO-1 antibody at a fixed dose of about 10-3000 mg the claimed invention every 2 to 4 weeks, which is a broad range of dose to be administered to a subject.
***
Response to Amendments
Applicant does not offer further arguments regarding the above obviousness rejections beyond what was set forth with regard to the 35 U.S.C 102 rejection above. To extend the Applicant is merely repeating their previous argument, the Examiner contends that those issues were adequately addressed in above sections, which are incorporated in their entireties herein by reference.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Advisory Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PRICILA HAUK TEODORO whose telephone number is (571)272-2784. The examiner can normally be reached M-F 6:15AM-3:00PM.
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/PRICILA NMN HAUK TEODORO/Examiner, Art Unit 1645
/HEATHER CALAMITA/Supervisory Patent Examiner, Art Unit 1684
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