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 .
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement(s) (IDS) was/were submitted on 6/8/2023, 12/17/2024, and 10/30/2025, before the mailing of a first office action. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Status
Claims 1-9, filed 6/24/2024, are pending. Claims 1-9 are under examination.
Specification
The use of the term “Blue Sepharose”, on page 16, para. [0062], which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
The use of the term “Vivaspin Turbo”, on page 16, para. [0062], page 17, para. [0067], which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 1 is objected to because of the following informalities. Claim 1 recites “A method for activating macrophage, …”. Amending “macrophage” to “macrophages” would result in better sentence structure. Also, “macrophage cells” would also be acceptable. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 3 is 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.
Regarding claim 3, claim 1 already precludes the claimed Gc protein from having any N-acetylgalactosamine from being attached. It is not clear why specific amino acid positions are recited as not having N-acetylgalactosamine attached. Furthermore, the phrase “… wherein the Gc protein, an amino acid to which N-acetylgalactosamine is not attached…” gives the impression that the Gc protein is an amino acid, when it is a polypeptide. Applicant might consider an amendment to: “The method according to claim 1, wherein the Gc protein consists of the sequence SEQ ID NO: 1”.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 4 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 cancer treatment, infectious disease treatment, autism treatment, skin improvement, of hypertension, cardiac hypertrophy, fibrosis, adverse cardiac remodeling and cardiac dysfunction heart diseases, Alzheimer’s, Parkinson’s, Multiple Sclerosis, and Chronic Fatigue Syndrome does not reasonably provide enablement for any possible brain/neuro-degenerative disease, any possible inflammatory disease, any possible heart disease or any possible autoimmune 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.
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is "reasonable" or is "undue." Consistent with Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Wands factors continue to provide a framework for assessing enablement in a utility application or patent, regardless of technology area. Guidelines for Assessing Enablement in Utility Applications and Patents in View of the Supreme Court Decision in Amgen Inc. et al. v. Sanofi et al., 89 FR 1563 (January 10, 2024). These factors include, but are not limited to:
The breadth of the claims;
Claim 4 is extremely broad with respect to the broad category of diseases listed.
The nature of the invention;
The invention is a method for activating macrophages, comprising administering to a subject a Gc protein with no N-acetylgalactosamine attached.
The state of the prior art;
Regarding autoimmune diseases and inflammatory diseases, Morales (Morales, Eric Matamoros World Scientific News 65:20-36 (2017)) discloses that: “Even the big potential of GcMAF, big companies claim the high effect of this molecule to threat other diseases which affect the immune system response. This makes sense as the possibility of reactivating immune system to attack Mycobacterium tuberculosis, the main tuberculosis agent, modulate it in proinflammatory and autoimmune diseases such as Chron’s disease, or even attack viral infections including Dengue and Malaria. Unfortunately, there is no proven data and neither published reports in any known journal to contrast the effectiveness of GcMAF in those diseases, so further studies are required to prove it.” (Morales, page 29, para. 3).
Regarding neurodegenerative disease, Morales discloses the usage of GcMAF for the treatment of Alzheimer’s, Parkinson’s, Multiple Sclerosis, and Chronic Fatigue Syndrome (Morales, page 28, para. 1). However, this does not encompass other neurodegenerative diseases such as ALS or traumatic brain injury as disclosed by Amor (Amor, Sandra, et al. Immunology 129.2: 154-169, page 161, Table 3).
Regarding heart diseases, Kain et al. discloses that macrophages are involved in some heart disease treatments: “Our findings highlight the central role of macrophages in the pathogenesis of hypertension, cardiac hypertrophy, fibrosis, adverse cardiac
remodeling and dysfunction.” (Kain et al., page 393, col. 2, para. 3). However, this doesn’t necessarily extend to conditions like atherosclerosis of the cardiac blood vessels or acute ischemia.
The level of one of ordinary skill;
A person of ordinary skill in the art typically would possess at least a Master’s level education and frequently a Ph.D.
The level of predictability in the art;
The predictability regarding the efficacy of GcMAF treatments is currently low. Morales summarizes the current state of GcMAF treatments: “Since the last decade there has been a wide controversy involving GcMAF treatment and its claimed effectiveness. The main reasons against GcMAF is that clinical trials lack of significant data, because of the small-group of patients treated in the studies, involving fewer than twenty patients in each, rather than the hundreds or thousands that are required to obtain a reliable conclusion. Patients in many of those trials have previously received other treatments such as chemotherapy, surgery or derivate. Other controversies are related in the fact that during the studies only Nagalase levels are monitored during GcMAF treatment and change in tumoral markers are not taking into account. There is also no proven detail about the TNM (tumour, node, metastasis) status (measure to determine cancer spread in patients). The fact that GcMAF studies were published in a medium-journal instead of in a top-tier ‘high impact’ journal also disappoints scientists as it decreases credibility. Retraction also makes the paper dubious. To sum up, a lot of web pages have claimed this molecule as the ‘cure’ that everyone expects to treat all type of diseases without providing journals to contrast their information.” (Morales, page 29 para. 4).
(F) The amount of direction provided by the inventor and the existence of working examples and the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
A tremendous amount of experimentation would be required to test the efficacy of GcMAF against all the claimed disease states. As discussed by Morales above, significant questions already exist with respect to the efficacy of GcMAF and they have not been resolved in the 20+ years of GcMAF studies and research papers.
Regarding claim 4, many disease states have support in the prior art; however the rejected disease states are the cases in which disease states are claimed for which support is lacking. The issue of unpredictability is exacerbated by sources such as Morales, which cast some doubt on the breadth of treatment coverage provided by GcMAF treatment. Consequently, 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 and claim 4 is rejected.
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.
Claim 5 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yamamoto et al. (Yamamoto, et al. Translational oncology 1.2: 65-72 (2008).
Regarding claim 5, claim 5 recites a method of producing a macrophage activator, comprising bringing a Gc protein into contact with N-acetylgalactosaminidase. Yamamoto et al. describes such a process:
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(Yamamoto et al., page 66, Fig. 1b).
Consequently, claim 5 is anticipated by Yamamoto et al. and rejected.
Claim Rejections - 35 USC § 103
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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Yamamoto et al. (Yamamoto, et al. Translational oncology 1.2: 65-72 (2008)) in view of Nabeshima et al. (Nabeshima, et al. Scientific Reports 10.1: 19122 (2020)).
Yamamoto discloses a method of activating macrophages by administering enzymatically treated Gc proteins: “Serum Gc protein (known as vitamin D3–binding protein) is the precursor for the principal macrophage-activating factor (MAF). The MAF precursor activity of serum Gc protein of prostate cancer patients was lost or reduced because Gc protein was deglycosylated by serum α-N -acetylgalactosaminidase (Nagalase) secreted from cancerous cells. Therefore, macrophages of prostate cancer patients having deglycosylated Gc protein cannot be activated, leading to immunosuppression. Stepwise treatment of purified Gc protein with immobilized β-galactosidase and sialidase generated the most potent MAF (termed GcMAF) ever discovered, which produces no adverse effect in humans. Macrophages activated by GcMAF develop a considerable variation of receptors that recognize the abnormality in malignant cell surface and are highly tumoricidal. Sixteen nonanemic prostate cancer patients received weekly administration of 100 ng of GcMAF.” (Yamamoto et al., Abstract).
Yamamoto does not disclose the case wherein the Gc protein without N-acetylgalactosamine attached is administered to a subject. However, Nabeshima et al. discloses that the Gc2 variant of Gc protein has phagocytic activation activity: “ Furthermore, Gc1S and Gc2 were also synthesized as phagocytosis-activation active forms in ExpiCHO-S cells (Fig. 6). As expected, Gc1F and Gc1S were reactive with HPA and VVA-lectins. However, Gc2 (T420K mutation) was not. This suggests that (1) HPA-lectin-reactive saccharide may be not essential for the phagocytosis-activation activity of Gc2 protein, at least in vitro, and (2) if so, Gc2 synthesized in ExpiCHO-S cells may act as a phagocytosis-activation factor via a mechanism not involving GalNAc.” (Nabeshima et al., page 6, para. 1).
Importantly, the Gc2 version of the Gc protein has a T240K substitution which completely precludes the possibility of glycosylation:
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(Nabeshima et al., page 2, Fig. 1)
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the Gc2 protein sequence in place of the conventional Gc1F or Gc1S sequence to arrive at the claimed invention.
A person of ordinary skill in the art would have a reasonable expectation of success because Nabeshima describes their process as creating Gc proteins suitable for clinical usage: “In conclusion, we established methodology to produce biologically active GcMAF in large quantities by overexpressing Gc proteins in ExpiCHO-S cells under serum-free suspension culture conditions. Notably, the synthesized GcMAF can be purified in a single step by means of vitamin D affinity column chromatography. This simple protocol is expected to be suitable for large-scale production of high-quality GcMAF for functional analysis and clinical testing.” (Nabeshima et al, page 7, para. 2). Therefore, the Gc2 protein of this disclosure may be substituted in for the Gc proteins used in Yamamoto to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to combine these disclosures in order to be able to skip the deglycosylation steps described as necessary by Yamamoto: “ Stepwise incubation of the purified Gc protein with immobilized β-galactosidase and sialidase yielded probably the most potent MAF (GcMAF) ever discovered [21–23] (Figure 1c). The immobilized enzymes were removed by centrifugation. Thus, GcMAF is pure and free from contamination of the enzymes. The final product, GcMAF, was filtered through a low protein-binding filter, Millex-HV (Millipore Corp., Bedford, MA) for sterilization.” (Yamamoto et al., page 67, col. 1, para. 3).
Consequently, claim 1 is obvious over Yamamoto et al. in view of Nabeshima et al. and rejected.
Regarding claim 9, claim 1 is obvious as described above. Yamamoto and Nabeshima do not explicitly disclose the case wherein a dosage in terms of the total protein content per kilogram of the subject's weight is 0.1 mg to 4.0 mg.
However, the MPEP 2144.05(II)(A) states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).”
The present specification does not appear to provide any data that shows the criticality of this dosage range. Consequently, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to discover and use a dosage regime of 0.1 mg to 4.0 mg per kilogram of body weight through routine experimentation. Consequently, claim 9 is obvious over Yamamoto et al. in view of Nabeshima et al. and rejected.
Claim 2 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yamamoto et al. (Yamamoto, et al. Translational oncology 1.2: 65-72 (2008)) in view of Nabeshima et al. (Nabeshima, et al. Scientific Reports 10.1: 19122 (2020)) as applied to claim 1 above, and further in view of Morita et al. (Morita, et al. Protein Expression and Purification 175:105714 (2020)).
Regarding claim 2, claim 1 is obvious as described above. Claim 2 further recites the case wherein the Gc protein is purified from serum or milk of human, a cow, a goat, or a mouse. Yamamoto and Nabeshima do not specifically disclose this limitation.
However, Morita et al. discloses that Gc2 can be purified from human serum: “In the present study, we successfully purified Gc protein from human serum using anion-exchange chromatography and confirmed the subtypes of the purified Gc protein to be Gc1F and Gc2.” (Morita et al., page 6, col. 1, para. 2; page 4, Fig. 3b).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to purify the Gc2 protein for use in the method of Yamamoto and Nabeshima using human serum as a source of Gc2 protein as described by Morita. A person of ordinary skill in the art would be motivated to use human serum as a source of Gc2 to have an alternative source of Gc2 available (instead of relying exclusively on CHO cells) and would have a reasonable expectation of success because Morita describes the exact process of purifying Gc2 from human serum (Morita et al., page 2, entirety of section 2). Consequently, claim 2 is obvious over Yamamoto et al. in view of Nabeshima et al. as applied to claim 1 above, further in view of Morita et al. and rejected.
Allowable Subject Matter
Claims 6-8 are not currently rejected.
The following is a statement of reasons for the indication of allowable subject matter.
Regarding claim 6, no suggestion or motivation to put a neuraminidase (sialidase) step before an N-acteylgalactosaminidase step can be found in the prior art. A sialidase step in conjunction with a galactosidase step is associated with production active GcMAF material: “Stepwise treatment of purified Gc protein with immobilized β-galactosidase and sialidase generates the most potent MAF (termed GcMAF) [20–24] (Figure 1c), which produces no adverse effects in humans.” (Yamamoto et al., page 66, col. 2, para. 2). Conversely, an N-acteylgalactosaminidase step is associated with deactivation of the Gc protein: “However, the MAF precursor activity of prostate cancer patient Gc protein is lost or reduced, because their serum Gc protein is deglycosylated by serum α-N-acetylgalactosaminidase (Nagalase) secreted from cancerous cells [25,26] (Figure 1b).” (Yamamoto et al., page 66, col. 1, para. 1). Therefore, adding this step to the process of claim 5 makes the process free of the prior art.
Regarding claim 7, the Gc protein used to in the rejection of claim 1 is Gc2 protein. Gc protein lacks any sugars at the 420 position because of a threonine to lysine substitution. Consequently, no motivation exists to bring this protein into contact with N-acetylgalactosaminidase. Therefore, adding this limitation to claim 1 makes the process free of the prior art.
Regarding claim 8, claim 7 is free of the prior art as described above. Claim 8 is dependent upon claim 7 and therefore also free of the prior art.
Claims 6-8 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
No claim is allowed.
Claims 1-5 and 9 are rejected.
Claims 1 and 6-8 are objected to.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to David Paul Bowles whose telephone number is (571)272-0919. The examiner can normally be reached Monday-Friday 8:30-5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko Garyu can be reached on (571) 270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DAVID PAUL BOWLES/Examiner, Art Unit 1654
/LIANKO G GARYU/ Supervisory Patent Examiner, Art Unit 1654