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 .
Restriction/Election
Applicant’s election without traverse of the species, SEQ ID NO: 5 and LGM2B, in the reply filed on 07/08/26 is acknowledged.
Claims 9, 11, 15-18, 20 and 27 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/08/26. The search revealed art that also reads on SEQ ID NO: 1, which will be included as well (claims 9 and 25).
Claims 1-10, 12-14, 19 and 21-26 are under examination. An Office action on the merits follows.
Claim Rejections 35 USC 112(A)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-10, 12-14, 19 and 21-26 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 treating and polarizing macrophages in LGMD2B with a full length Gal-1 proteins, it does not reasonably provide enablement for treating all diseases associated with canonical inflammation or treating any disease or polarizing macrophages to an M2 phenotype with a fragment of Galectin protein. 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 and use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These factors include, but are not limited to: (1) The breadth of the claims; (2) The nature of the invention; (3) The state of the prior art; (4) The level of one of ordinary skill; (5) The level of predictability in the art; (6) The amount of direction provided by the inventor; (7) The existence of working examples; and (8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988) (reversing the PTO's determination that claims directed to methods for detection of hepatitis B surface antigens did not satisfy the enablement requirement). In Wands, the court noted that there was no disagreement as to the facts, but merely a disagreement as to the interpretation of the data and the conclusion to be made from the facts. In re Wands, 858 F.2d at 736-40, 8 USPQ2d at 1403-07. The Court held that the specification was enabling with respect to the claims at issue and found that "there was considerable direction and guidance" in the specification; there was "a high level of skill in the art at the time the application was filed;" and "all of the methods needed to practice the invention were well known." 858 F.2d at 740, 8 USPQ2d at 1406. After considering all the factors related to the enablement issue, the court concluded that "it would not require undue experimentation to obtain antibodies needed to practice the claimed invention." Id., 8 USPQ2d at 1407.
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. leva 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 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). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorerlnc., 49 USPQ2d 1370.
The analysis is as follows:
(1) The nature of the invention and (5) The breadth of the claims:
The claims are drawn to treating any NF-kB canonical inflammation associated disease with any fragment of a galectin protein. However, the specification only shows one embodiment of treating LGM2B NF-kB canonical inflammation in BAL/J mice, which is specifically for treating LGM2B with rHsGal-1 (recombinant) and Wild Type Gal-1 (examples 1-5).
As to treating a disease or shifting to an M2 phenotype with a fragment of galectin protein, this includes an even broader class of subjects, as it only requires administration to a subject having M1 inflammation that can shift to M2, not a particular disease.
The limitation “a fragment thereof,” is extremely broad. The specification defines fragment as “any peptide containing a portion of the galectin-1 protein amino acid sequence (SEQ ID NO: 1).” This includes portions as short as two amino acids, absent any limiting definition. The activity of two Gal-1 residues versus the full length protein differs significantly. The results presented in the specification for membrane repair found that the carbohydrate recognition domain (CRD) of Gal-1 is necessary for improving repair capacity [0061, examples 1-3]. These examples also show that not all not all dosing regimens were effective. For example, example 5 showed that dosing at 27 mg/kg 2x/wk only had minor benefits to membrane repair, suggesting this dose was inadequate to provide the full benefit, whereas a very high dose treatment (27mg/kg 3x/wk) made membrane repair worse in the animals.
of the administered peptide can be one of Ala-Thr, Gly-Gly, Cys-Cys, etc. This would not be expected to have the same activity as the 400-800 residue galectin of SEQ ID NOs: 1-5.
(2) The state of the prior art:
The art recognizes that “the nuclear factor-kappa B (NF-kappaB) signaling pathway is a multi-component pathway that regulates the expression of hundreds of genes that are involved in diverse and key cellular and organismal processes, including cell proliferation, cell survival, the cellular stress response, innate immunity and inflammation. Not surprisingly, mis-regulation of the NF-kappaB pathway, either by mutation or epigenetic mechanisms, is involved in many human and animal diseases, especially ones associated with chronic inflammation, immunodeficiency or cancer” (Courtois, G and Gilmore, T.D. Oncogene. 2006, Oct 30;25(51):6831-43; Abstract). Therefore, treatment of NF-kB “associated” diseases extremely broad in that such treatment includes many diseases that are chronically activated NF-kB canonical pathway in many inflammatory diseases, such as inflammatory bowel disease, arthritis, sepsis, gastritis, asthma, atherosclerosis and others (Park et al. Cells. 2016, Vol. 5, No. 15).
Cancer is also well known to be associated with NF-kB canonical inflammation pathway. Specifically, the prior art shows that there never has been a compound capable of treating cancers generally. The decision of In re Application of Hozumi et al., 226 USPQ 353 addresses the enablement of cancer generally, stating: “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.”As such, there are compounds that treat a modest range of cancers, but none has ever been effective against cancer generally, or even a majority of cancers.
Furthermore, many diseases and conditions associated with NF-KB canonical inflammation have had decades of reasearch, but no successful treatments have been developed as of today. For example, obesity associated with canonical inflammation is known to be associated with NF-KB canonical inflammation (Petrascu et al. Biomedicines 2025, 13, 3050). Petrascu teaches that despite decades of research, no NF-κB targeted therapy has yet achieved clinical approval for obesity (abstract). The main obstacles include the essential physiological roles of the NF κB pathway, the difficulty of achieving tissue specificity, and the heterogeneity of human obesity (abstract). According to Petrascu, “Future progress will depend on identifying biomarkers that define NF-κB driven obesity phenotypes, refining tissue-targeted delivery platforms, and conducting longer, more carefully stratified clinical trials. Precision medicine approaches integrating genetic, transcriptomic, and metabolomic data will likely guide the next generation of therapeutics aimed at the immunometabolism axis” (Abstract).
This is far from administering a fragment of galectin protein for treatment of any subject having any of the above conditions or shifting to the M2 phenotype of inflammation in all diseases associated with canonical inflammation.
(3) The relative skill of those in the art:
The relative skill of those in the art is high because of the complex nature of treating all NF-kB canonical inflammation associated diseases or polarizing macrophages to an M2 phenotype in any subject, and the inefficacy of treating broadly inclusive and variant class of patients with a highly variant galectin protein fragment.
. Case law addresses skill in the art through various decisions, such as In re Novak, 134 USPQ 335, 337-338, which states “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. Even if applicants’ assertion that al NF-kB canonical inflammation associated disease and polarizing macrophages in general could be treated with any Galectin protein or Gal-1 fragment were plausible— which it is not —, that would not suffice, as was stated in Rasmusson v. SmithKIine 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.”
(4) The predictability or unpredictability of the art:
The level of predictability in the art is low, given that the fragment of Galectin protein can be as short as four amino acids of any portion of any galectin protein. For example, regarding physiological activity, 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, this invention is directed towards therapeutics for treating any disease that may be associated with o NF-kB canonical inflammation, which as discussed above, includes many diseases with different etiologies, symptoms and mechanisms which are 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).
(6) The amount of direction or guidance presented and (7) The presence or absence of working examples:
There is no guidance for treating NF-kB canonical inflammation with fragments of Galectin proteins. There is also no guidance for the vast majority of diseases that are associated with canonical NF-kB inflammation, aside from LGM2B treatment and those requiring membrane repair. Additionally, the examples do not provide support to show how all known galectin proteins or any size fragment of SEQ ID NO: 1 affect canonical inflammation biomarkers or treat all of such disease by showing other markers of efficacy.
The 5 working examples to not provide adequate support, as they only utilize wild type and recombinant Gal-1 for treating inflammation to promote membrane repair or to treat LGM2B. This is insufficient guidance and few examples to cover the broad genera of diseases and fragments that are claimed.
(8) The quantity of experimentation necessary:
Because it is uncertain to predict what new cancer treatment will be effective for various NF-kB canonical inflammation associated disease, and especially in view of factors 1-7, the quantity of experimentation needed to make and use the claimed invention is expected to be extremely high, as the predictability is very low.
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.
Claim Rejections 35 USC 102(A)(1)
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-5, 7-10, 12-14, 19 and 21-26 are rejected under 35 U.S.C. 102(A)(1) as being anticipated by Rathgeber, Matthew F., (Galectin-1 Improves Sarcolemma Repair and Decreases the Inflammatory Response in LGMD2B Models. 2020. Theses and Dissertations. 8723).
Rathgeber teaches galectin-1 (Gal-1), a soluble carbohydrate binding protein, increases membrane repair capacity, myogenic potential, M2 macrophage polarization and decreases NF-κB inflammation in dysferlin-deficient models (abstract). This reference teaches recombinant human galectin-1 (rHsGal-1) to treat dysferlin-deficient models of LGMD2B (Abstract). Rathgeber teaches that rHsGal-1 treatments of 48 h-72 h promote myogenic maturation as indicated through improvements in size, myotube alignment, and myoblast migration in dysferlin-deficient myotubes and showed an increased membrane repair capacity of dysferlin deficient myotubes (abstract). Rathgeber teaches that improvements in membrane repair after only a 10 min rHsGal-1 treatment suggests mechanical stabilization of the membrane due to interaction with glycosylated membrane bound, ECM or yet to be identified ligands through the CDR domain of Gal-1 (abstract). This reference finds that 2.7 mg/kg in vivo rHsGal-1 treatment in BLA/J (LGMD2B model) of mice supports an M2 cyto-regenerative macrophage populations (abstract).
This reference further teaches that 1wk in vivo 2.7 mg/kg rHsGal-1 treatment in mice (in rHsGal-1 treated mice receiving a weekly dose of 2.7 mg/kg, 26.2% of macrophages expressed CD206 (M2) and 20.4% expressed CD86(M1) whereas PBS treated mice showed 3.4% of macrophages expressed CD206 and 62.7% expressed CD86 (Fig 3.2.3-1D-F), suggesting that rHsGal-1 need participating cytokines or immune cells to polarize Macrophages into an M2 or M1 phenotype (p. 44). However, this reference teaches that Overton Precent positive analysis subtracts the control fluorescence from the sample in each channel and sums the number of remaining events which provides a percentage of positive cells and the Overton % positive value for CD206 and CD86 was 24.9% and 0.4%, respectively (Fig 3.2.3-1G-H.). These preliminary results suggest that rHsGal-1 can effectively polarize resident macrophage to an M2 phenotype in LGMD2B in vivo models (p. 44, para. 1).
Claims 1, 14 and 19 are met because rHsGal-1 treatment was performed in BLA/J mice (LGMD2B model), which is taught to be associated with NF-kB canonical inflammation. and meets the elected species LGMD2B, recited in claims 14 and 19. Claims 2-5 are met because Rathgeber teaches intraperitoneally administering Gal-1 at 2.7mg/kg for 48-72 hours, which falls within the claimed dosage range for intraperitoneal administration. Claims 21-26 are met by intraperitoneal administration of 2.7 mg/kg Gal-1 protein (SEQ ID NO: 1) because Rathgeber teaches rHsGal-1 can effectively polarize resident macrophage to an M2 phenotype in LGMD2B in vivo models when administered at 2.7mg/kg interperitoneally and also teaches mGal as an effective galectin protein in this method. Claims 7-10 are met because Rathgeber teaches Gal-1 (SEQ ID NO:1) and mGal (SEQ ID NO: 5). Claim 13 is met because the mice were dosed weekly (p. 44). Claim 12 is met because dysferlin deficient mice were given 48-72 hours treatments, which falls within the scope of a daily dosing regimen as well.
Claim(s) 1-5, 7-9, 13 and 14 are rejected under 35 U.S.C. 102(A)(1) as being anticipated by Burkin et al. (US2015/0196618).
Burkin teaches methods of treating patients with muscular dystrophy, such as merosin deficient congenital muscular dystrophy Type 1A, limb-girdle muscular dystrophy, facioscapulohumeral muscular dystrophy, Beckers muscular dystrophy and Duchenne muscular dystrophy with galectin-1 protein [0006-0007]. This reference further teaches intraperitoneal and intravenous administration of Gal-1 [claims 7-9]. This reference also specifically reduces to practice a method of intraperitoneally administering 5mg/kg to mice to decrease muscle damage in DMD muscle dystrophy models of MDX mice [0321-0324].
This meets the limitation of claim 1 by teaching Gal-1 administration to the same patient class of those having chronic NF-kB canonical inflammation. As to the limitation “associated with NF-kB canonical inflammation,” muscular dystrophy is the patient class, meaning that the same galectin-1 protein is being administered to the same class of subjects having muscular dystrophy. MPEP 2112 states: "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). In In re Crish, 393 F.3d 1253, 1258, 73 USPQ2d 1364, 1368 (Fed. Cir. 2004), the court held that the claimed promoter sequence obtained by sequencing a prior art plasmid that was not previously sequenced was anticipated by the prior art plasmid which necessarily possessed the same DNA sequence as the claimed oligonucleotides. The court stated that "just as the discovery of properties of a known material does not make it novel, the identification and characterization of a prior art material also does not make it novel." Id.
As such, the same Gal-1 protein is administered to the same class of subjects having muscular dystrophy.
Claims 2-5 are met because Burkin teaches 5mg/kg to 20mg/kg either weekly or biweekly intraperitoneal or systemic administration [0324, claims 6 and 8]. Claims 7-9 are met because Burkin teaches Gal-1, SEQ ID NO: 1. Claims 13 and 14 are met because Burkin teaches treating muscular dystrophy weekly.
Claim(s) 1 and 6-9 is/are rejected under 35 U.S.C. 102(A)(1) as being anticipated by Carlos et al. (Scientific Reports. Pharmacological treatment with galectin-1 protects against renal ischemia-reperfusion injury (2018) 8:9568), as evidenced by Zhang and Sun (Cell Biosci. (2015). Vol. 5:63).
Carlos teaches that Galectin-1 protein (GAL-1) has important anti-inflammatory properties, but related pharmacologic approaches to effectively treat or prevent renal ischemia and reperfusion injury are highly limited, but this study found that in a renal ischemia-reperfusion injury rat model and an in vitro hypoxia-reoxygenation model with a proximal renal tubular epithelial cell line the intravenous administration of intraGAL-1 was effective to reduce macrophage and neutrophil influx into the renal interstitium of the juxtamedullary region under the IR condition (Abstract). This reference teaches that recombinant human GAL-1 was administered at a dose of 100 μg/animal to 200-250g male Wistar rats (p. 9, para. 1-3). This reference teaches that Gal-1 was administered intravenously 30 min before surgery and the untreated IR group received only phosphate-buffered saline (p. 9, para. 2).
This meets the limitations of claims 1 and 6 by teaching intravenous administration of GAL-1 at a dose of .4-.5mg/kg, based on the disclosed dosage and animal weight. As to the limitation “associated with NF-kB canonical inflammation,” this is heavily involved in the etiology of renal ischemia and reperfusion, as evidenced by Zhang and Sun, showing that ischemia–reperfusion induces the production of TNF-α in an NF-κB-dependent manner, and TNF-α in turn binds to its receptor to stimulate NF-κB activation, thereby providing a positive feedback mechanism of NF-κB regulation in ischemia-reperfusion that plays an important role in the pathogenesis of renal ischemia–reperfusion injury (Cell Biosci. (2015) 5:63). As such, administration of Gal-1 intravenous to treat a disease associated with the NF-kB conical inflammation is anticipated. Claims 7-9 are met by Carlos teaching Gal-1 as the galectin protein to administer.
Conclusion
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/JEANETTE M LIEB/Primary Examiner, Art Unit 1654
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