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 1-2, 4-5, and 7-9, filed 4/9/2026, are pending. Claims 1-2, 4-5, and 7-9 are under examination. Claims 3 and 6 are canceled.
Claim Interpretation
Amended claim 1 is interpreted to recite the case wherein no N-acetylgalactosamine is attached to threonine at position 420 in SEQ ID NO: 1, when threonine is present at position 420. However, there is no requirement thatthreonine at position 420 must be present in the claimed Gc proteins having at least 90% sequence identity to SEQ ID NO: 1.
Specification
The specification was objected to for the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks).
Response to Arguments
Applicant’s arguments, see Applicant Reply, page 7, para.2 filed 4/9/2026, with respect to objections to the specification have been fully considered and are persuasive. The objection to the specification has been withdrawn.
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
Claim 3 was 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.
Response to Arguments
Claim 3 has been canceled, rendering this rejection moot.
Claim Rejections - 35 USC § 112
Claims 4 was previously rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
Response to Arguments
Applicant’s arguments, see Applicant Reply, page 8, para. 3, filed 4/9/2026, with respect to claim 4 have been fully considered and are persuasive. The rejection of claim 4 has been withdrawn.
New Claim Rejections - 35 USC § 112
Claims 1, 2, 4, and 9 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.
Claim 1 recites a method for activating macrophage, comprising administering to a subject a Gc protein, with no N-acetylgalactosamine attached thereto wherein the Gc protein has at least 90% sequence identity to the amino acid sequence of SEQ ID NO:1, and wherein no N-acetylgalactosamine is attached to threonine at position 420 in SEQ ID NO:1.
90% sequence identity allows for 45 substitutions in a 458 amino acid protein. This creates a sequence space of at least 20^45 proteins claimed by claim 1 which must be able to perform the claimed method.
In this case, 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 inventor was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. (MPEP § 2163 (II.A.3.a.ii.))
According to MPEP § 2163 (II.A.3.a.ii.), 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. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014).
As described above, claim 1 recites an extremely large genus of proteins.
MPEP § 2163 (II.A.3.a.ii.) states that “for inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’”
Even when several species are disclosed, these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, as here, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. Since each genus recited in the instant claims is large, it would be very challenging to describe sufficient species to cover the structures of the entire genus.
Applicant discloses SEQ ID NO: 1, the canonical Gc protein. Because the Gc protein was prepared from human serum, presumably the original protein has threonine with N-acetylgalactsoamine. Applicant’s disclosed method then removes acetylgalactosamine with treatment with N-acetylgalatosaminidase. Macrophages were shown to be activated by the result of this process, but no other proteins were tested.
At the time of the effective filing date of the claimed invention., the level of skill for preparing proteins with desired functional properties was high. However, even if a synthesis and selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identify peptides that yield polypeptides with the recited properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010); see also Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1876 (Fed. Cir. 2011) (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”) Absent the conserved structure (length) provided by the provided species, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what peptide with a particular set of properties would look like structurally.
Only one example is disclosed. Therefore, the provided examples only represent a limited structural diversity.
Since only a limited number of species of proteins are taught within the claimed genus above, the instant claim above fails the written description requirement. A representative number of species has not been taught to describe this genus. Regarding the proteins, a single point mutation can change the biophysical properties of a peptide: “In summary, we have shown that the structural changes in the fibrillar state of the Aβ42 peptide that are observed to occur upon introduction of single point mutations can be accompanied by changes in the dominance of the microscopic processes by which these aggregates are themselves formed.” (Bolognesi et al. ACS Chem Bio 9:2 (2013) page 381 col. 2 para. 3) and “In summary, while ovispirin-1 and novispirin G-10 both had solution structures that were helical and amphipathic in the presence of TFE, a relatively simple change in their primary structure (a single glycine–isoleucine exchange) had profound effects on their respective toxicities for human erythrocytes and epithelial cells.” (Sawai et al. Protein Eng. 15:3 (2002) page 232 col. 1 para. 3).
Furthermore, many sequences allowed by the current scope of the claims, result in non-functional aggregates. Wang (Wang, et al. MAbs. Vol. 1. No. 3. Taylor & Francis, (2009)) discloses a variety of aggregation prone motifs that occur in commercial antibodies (Wang, page 262, Table 2). The scope of the claims currently may incorporate such motifs and result in non-functional aggregates.
Given this unpredictability of protein design, the skilled artisan would not have been in possession of the substantial repertoire of protein species encompassed by the claimed invention; one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genus of every protein molecule disclosed by claim 1.
Consequently, claim 1 is rejected.
Regarding claim 2, 4, and 9, these claims do not reduce the genus size of the claimed protein genus. Therefore, one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genus of every protein molecule disclosed by these claims.
Consequently, claims 2, 4, and 9 are rejected.
Claim Rejections - 35 USC § 102
Claim 5 was previously 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).
Response to Arguments
Applicant’s arguments, see Applicant Reply, page 9, para. 3, filed 4/9/2026, with respect to claim 5 have been fully considered and are persuasive. The rejection of claim 5 has been withdrawn.
Claim Rejections - 35 USC § 103
Response to Arguments
Applicant’s arguments, see Applicant Reply, page 10, para. 1, filed 4/9/2026, with respect to the rejection of claims 1, 2, and 9 under U.S.C. 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground of rejection is made below.
New 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.
Claim 1 is 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)) and UniProt Accession No. P02774 · VTDB_HUMAN (uploaded 1992, accessed 6/23/2026).
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).
Applicant SEQ ID NO: 1 is aligned against UniProt P02774 below:
#=======================================
#
# Aligned_sequences: 2
# 1:
# 2:
# Matrix: EBLOSUM62
# Gap_penalty: 10.0
# Extend_penalty: 0.5
#
# Length: 458
# Identity: 458/458 (100.0%)
# Similarity: 458/458 (100.0%)
# Gaps: 0/458 ( 0.0%)
# Score: 2431.0
#
#
#=======================================
1 LERGRDYEKNKVCKEFSHLGKEDFTSLSLVLYSRKFPSGTFEQVSQLVKE 50
||||||||||||||||||||||||||||||||||||||||||||||||||
1 LERGRDYEKNKVCKEFSHLGKEDFTSLSLVLYSRKFPSGTFEQVSQLVKE 50
51 VVSLTEACCAEGADPDCYDTRTSALSAKSCESNSPFPVHPGTAECCTKEG 100
||||||||||||||||||||||||||||||||||||||||||||||||||
51 VVSLTEACCAEGADPDCYDTRTSALSAKSCESNSPFPVHPGTAECCTKEG 100
101 LERKLCMAALKHQPQEFPTYVEPTNDEICEAFRKDPKEYANQFMWEYSTN 150
||||||||||||||||||||||||||||||||||||||||||||||||||
101 LERKLCMAALKHQPQEFPTYVEPTNDEICEAFRKDPKEYANQFMWEYSTN 150
151 YGQAPLSLLVSYTKSYLSMVGSCCTSASPTVCFLKERLQLKHLSLLTTLS 200
||||||||||||||||||||||||||||||||||||||||||||||||||
151 YGQAPLSLLVSYTKSYLSMVGSCCTSASPTVCFLKERLQLKHLSLLTTLS 200
201 NRVCSQYAAYGEKKSRLSNLIKLAQKVPTADLEDVLPLAEDITNILSKCC 250
||||||||||||||||||||||||||||||||||||||||||||||||||
201 NRVCSQYAAYGEKKSRLSNLIKLAQKVPTADLEDVLPLAEDITNILSKCC 250
251 ESASEDCMAKELPEHTVKLCDNLSTKNSKFEDCCQEKTAMDVFVCTYFMP 300
||||||||||||||||||||||||||||||||||||||||||||||||||
251 ESASEDCMAKELPEHTVKLCDNLSTKNSKFEDCCQEKTAMDVFVCTYFMP 300
301 AAQLPELPDVELPTNKDVCDPGNTKVMDKYTFELSRRTHLPEVFLSKVLE 350
||||||||||||||||||||||||||||||||||||||||||||||||||
301 AAQLPELPDVELPTNKDVCDPGNTKVMDKYTFELSRRTHLPEVFLSKVLE 350
351 PTLKSLGECCDVEDSTTCFNAKGPLLKKELSSFIDKGQELCADYSENTFT 400
||||||||||||||||||||||||||||||||||||||||||||||||||
351 PTLKSLGECCDVEDSTTCFNAKGPLLKKELSSFIDKGQELCADYSENTFT 400
401 EYKKKLAERLKAKLPDATPTELAKLVNKHSDFASNCCSINSPPLYCDSEI 450
||||||||||||||||||||||||||||||||||||||||||||||||||
401 EYKKKLAERLKAKLPDATPTELAKLVNKHSDFASNCCSINSPPLYCDSEI 450
451 DAELKNIL 458
||||||||
451 DAELKNIL 458
Therefore, Yamamoto discloses the case where the Gc protein has at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1.
Yamamoto does not disclose the case wherein no N-acetylgalactosamine is attached to threonine at position 420 in SEQ ID NO: 1.
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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452
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(Nabeshima et al., page 2, Fig. 1)
Furthermore, UniProt discloses Gc2 as a known variant of Gc protein that differs at only one position:
Variant position:
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24
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436Type of variant:
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24
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LB/BResidue change:
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From Threonine (T) to Lysine (K) at position 436 (T436K, p.Thr436Lys).Physico-chemical properties:
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24
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Change from medium size and polar (T) to large size and basic (K)BLOSUM score:
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24
24
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-1Polymorphism:
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24
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Over 80 variants of human DBP have been identified. The three most common alleles are called GC*1F, GC*1S, and GC*2. The sequence shown is that of the GC*1A1 allele.Variant description:
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24
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In allele GC*2, allele GC*2A9.Other resources:
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24
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Variant rs4588 [ dbSNP | Ensembl ]
Sequence informationVariant position:
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24
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436Protein sequence length:
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24
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474Location on the sequence:
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24
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TEYKKKLAERLKAKLPDATP T ELAKLVNKHSDFASNCCSINResidue conservation:
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Human TEYKKKLAERLKAKLPDATPTELAKLVNKHSDFASNCCSIN
Mouse TEYKKKLAERLRTKTPNTSPAELKDMVEKHSDFASKCCSIN
Rat TEYKKKLAERLRTKMPNASPEELADMVAKHSDFASKCCSIN
Bovine TEYKKKLAERLRGKFPDATETDLQELVAKRSDFASKCCSVN
Rabbit TEYKKKLSQQLRAKLPEATSAELAELVEKHSDFASKCCSIN
(UniProt P02774, accessed 6/23/2026).
Therefore, Gc2 has a 99%+ sequence identity with Applicant SEQ ID NO: 1 and reads on this claim.
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 because Gc2 possesses the desired activity and therefore this is a case of substitution of one known composition for another known composition for the same purpose.
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 UniProt and rejected.
Claim 2 is 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)) and UniProt Accession No. P02774 · VTDB_HUMAN (uploaded 1992, accessed 6/23/2026) 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 because Morita discloses that Gc2 can be purified from human serum.
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. and UniProt as applied to claim 1 above, further in view of Morita et al. and rejected.
Claim 4 is 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)) and UniProt Accession No. P02774 · VTDB_HUMAN (uploaded 1992, accessed 6/23/2026) as applied to claim 1 above, and further in view of Morales et al. (Morales, Eric et al. World Scientific News 65: 20-36 (2017)).
Regarding claim 4, claim 1 is obvious as described above. Claim 4 further recites the case wherein the subject is in need of cancer treatment, infectious disease treatment, autism treatment, Alzheimer's treatment, Parkinson's treatment, or skin improvement.
Yamamoto, Nabeshima, and UniProt do not disclose the case wherein the subject is in need of these specific treatments.
However, Morales et al. discloses that Gc protein can be used to treat Alzheimer’s disease:
“In other neurodegenerative diseases including Alzheimer’s and Parkinson’s disease Gc MAF therapy has also proved some benefits. 58 Most cases of Alzheimer and Parkinson involve the overproduction of Tumor necrosis factor alpha (TNF-α), a protein which promotes neuron death and interrupts synaptic communications, leading to the loss of memory or the uncontrolled spasms of the people that suffer this disorders. 55,56 GcMAF activate macrophages disable TNF- α interaction with neurons by occupying its receptors with stable bonds and avoiding neuronal death. Parkinson’s symptoms dropped by 60% but continuous revisions of the patients revealed the needed of continue the treatment to conserve this results and avoid a rebound of the disease. 50
Chronic Fatigue Syndrome (CFS) is also a neuronal condition characterized by long-term fatigue and other symptoms which relay on the decrease of the person’s ability to carry out ordinary daily activities. 54,60 It’s brought by different circumstances including weak immune system and stress conditions. People with CFS have elevate Nagalase levels up to 90%, meaning an immune system suppression. 55,59,60 Gc MAF treatment activated the macrophage response and reactivated again the whole immune system, leading to a partial recovery and improvement of near the 65% of the cases.” (Morales et al., page 28, para. 2).
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 method of Yamamoto, Nabeshima, and UniProt to treat Alzheimer’s disease because Morales teaches that Alzheimer’s can be treated by Gc-based therapy as described above.
A person of ordinary skill in the art would be motivated to do this Alzheimer’s disease is a serious condition that Morales discloses that Gc can treat and would have a reasonable expectation of success because Morales discloses that Gc protein can successfully treat this condition at least to some level as reported in the prior art.
Consequently, claim 4 is obvious over Yamamoto, Nabeshima, and Uniprot as applied to claim 1, further in view of Morales and rejected.
Claim 9 is 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)) and UniProt Accession No. P02774 · VTDB_HUMAN (uploaded 1992, accessed 6/23/2026) as applied to claim 1 above, and further in view of Pihl et al. (Pihl, et al. Basic & clinical pharmacology & toxicology 107.5: 853-860 (2010)).
Regarding claim 9, claim 1 is obvious as described above. Yamamoto, Nabeshima, and UniProt 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.
Yamamoto discloses a dosage of 100 ng of GcMAF per week: “Because the half-life of the activated macrophages is approximately 6 days [12,13], 100 ng of GcMAF was administered intramuscularly once a week.” (Yamamoto, et al., page 67, col. 2, para. 3).
Pihl et al. discloses that Gc protein is tolerated at much higher dosages of 20 mg/kg: “The ponies were treated in two separate periods. In the first period (period A), they were treated with PBS once a day for 14 days via the IV catheter. After a 7-day ‘wash out’ period, they were treated with Gc globulin (20 mg/kg) via the IV catheter once a day for 14 days (period B). In each treatment period, blood samples were collected, processed and analysed as described for the 14-day toxicity study in dogs.” (Pihl et al., page 856, col. 1, para. 3).
The horses of Pihl had no adverse side effects: “The ponies did not show any adverse clinical signs during the test period. Their appetite was unchanged and they did not lose weight. ECG and ophthalmoscopy examinations did not reveal any abnormal findings or changes during the test periods.
Clinical chemistry values were all within normal levels at all times monitored. Haematology and coagulation parameters did not change significantly during the test period. At necropsy, one pony had petechial bleedings in the thymus and the other had petechial bleedings in the adrenals. There were only minor non-significant changes seen at the microscopic examination. No vasculitis was observed.” (Pihl et al., page 858, col. 2, para. 1).
MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%."
It would have been obvious to a person of ordinary skill in the art before the effective filing date to use a concentration between the concentration disclosed by Yamamoto and the one disclosed by Pihl because these two concentrations establish an upper safe concentration and a known minimum at which efficacy occurs.
A person of ordinary skill in the art would be motivated to optimize such a concentration to illicit a stronger effect than that disclosed by Yamamoto and would have a reasonable expectation of success because Yamamoto shows efficacy at the lower concentration and the Pihl shows that the higher concentration is safe for large mammals.
Consequently, claim 9 is obvious over Yamamoto et al. in view of Nabeshima et al. and UniProt as applied to claim 1, and further in view of Pihl et al. and rejected.
Allowable Subject Matter
Claims 5, 7, and 8 are not currently rejected.
The following is a statement of reasons for the indication of allowable subject matter.
Regarding claim 5, 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 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. The prior art also shows that there is no motivation to deactivate the Gc protein by exposure to N-aceytlagalactosaminidase:
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(Yamamoto et al., page 66, Figure 1).
Therefore, this 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.
Conclusion
Claims 1, 2, 4, and 9 are rejected.
Claims 5, 7, and 8 are currently allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/DAVID PAUL BOWLES/Examiner, Art Unit 1654 /LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654
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