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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 07/21/2026 has been entered.
Withdrawal of Rejections
The response and amendments filed on 07/21/2026 are acknowledged. Any previously applied minor objections and/or minor rejections (i.e., formal matters), not explicitly restated here for brevity, have been withdrawn necessitated by Applicant’s formality correction and/or amendments. For the purposes of clarity of the record, the reasons for the Examiner’s withdrawal, and/or maintaining, if applicable, of the substantive or essential claim rejections are detailed directly below and/or in the Examiner’s Response to Arguments section.
Briefly, the previous claim rejections under 35 U.S.C. 103 for obviousness have been withdrawn necessitated by Applicant’s amendments; however, new grounds of rejection are set forth below.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 101
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 4 and 12are rejected under 35 U.S.C. 101 because they are drawn to ineligible subject matter (based on the 2019 Revised Patent Subject Matter Eligibility Guidance).
Broadest reasonable interpretation (BRI) of dependent claims 4 and 12: the broadest scope of claims 4 and 12 is drawn to comparing expression rates of N-acetylgalactosaminyltransferase 1 and 2.
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STEP 1: Is the claim directed to a process, machine, manufacture, or a composition of matter?
YES, the claims are directed to a process (method).
STEP 2A: PRONG ONE: Does the claim recite an abstract idea, law of nature, or natural phenomenon?
YES, the claims are considered to be an “abstract idea” (i.e., determining, evaluating, and/or comparing). Per MPEP 2106.04(a), an abstract idea can be a “mental process – concepts performed in the human mind (including an observation, evaluation, judgement, opinion)”. Claims 4 and 12 pertain to an abstract idea or method of comparing the expression rates of N-acetylgalactosaminyltransferase 1 and 2, which can be performed in the human mind.
PRONG TWO: Does the claim recite additional elements that integrate the judicial exception into a practical application?
NO, the additional elements or a combination of elements in the claims does not impose a meaningful limit on the judicial exception. Dependent claims 4 and 12 recite comparing expression rates between N-acetylgalactosaminyltransferase 1 and 2, which can be performed in the human mind. Moreover, claims 4 and 12 further recite “confirming that the N-acetylgalactosaminyltransferase 1 has a higher expression increase rate”; however, this does not integrate the judicial exception into practical application because this is merely another mental step that can be performed in the human mind that depends on the expression comparison step. Therefore, claims 4 and 12 are merely mental steps of comparing and confirming data, which do not integrate the judicial exception into practical application.
STEP 2B: Does the claim recite additional elements that amount to significantly more than the judicial exception?
NO, the claimed invention is directed to an abstract idea without significantly more. Note the claims must be interpreted under the BRI standard when evaluating for a marked difference. Under BRI, the claims broadly read on a mental method of comparing expression between N-acetylgalactosaminyltransferase 1 and 2.. There is no indication that the claimed invention has any differences from a mental process. Per MPEP 2106.04(a)(2)(III)(A), “claims do recite a mental process when they contain limitations that can practically be performed in the human mind, including, for example, observations, evaluations, judgements, and opinions”, wherein “a claim to “collecting information, analyzing it, and displaying certain results of the collection and analysis”, wherein the data analysis steps are recited at a high level of generality such that they could practically be performed in the human mind, Electric Power Ground v. Alstom, S.A., 830 F.3d 1350, 1353-54, 119 USOQ2d 1739, 1741-42 (Fed Cir. 2016)”.
Furthermore, comparing data is routine and conventional within the art (see, e.g., MPEP 2106.05(d)(II)). Sakai (Chondroitin Sulfate N-Acetylgalactosaminyltransferase-1 Plays a Critical Role in Chondroitin Sulfate Synthesis in Cartilage; 2006 –previously cited), teaches measuring N-acetylgalactosaminyltransferase 1 and N-acetylgalactosaminyltransferase 2 in cartilage (see, e.g., Sakai, Figure 2 & Results, pg. 4155). Sakai teaches that upon measuring N-acetylgalactosaminyltransferase 1 and N-acetylgalactosaminyltransferase 2 in developing mouse cartilage, chondroitin sulfate N-acetylgalactosaminyltransferase 1 is expressed at the highest level, while chondroitin sulfate N-acetylgalactosaminyltransferase 2 is expressed at very low levels (see, e.g., Sakai, Figure 2 & Results, pg. 4155). Therefore, comparing expression levels between N-acetylgalactosaminyltransferase 1 and 2 is a well-understood, routine, and conventional laboratory technique.
Therefore, the claims, as a whole, are considered an abstract idea (i.e., mental process) which are directed to judicially recognized exceptions without amounting to significantly more than what can practically be performed in the human mind and are not eligible under 35 U.S.C. 101.
Claim Rejections - 35 USC § 103, Obviousness
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-5 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Masuda (US 2013/0164383; Date of Publication: June 27, 2013 – previously cited) in view of Sakai (Chondroitin Sulfate N-Acetylgalactosaminyltransferase-1 Plays a Critical Role in Chondroitin Sulfate Synthesis in Cartilage; 2006 – cited in the IDS filed on 12/30/2024 & previously cited), and Sakai (Exhaustion of nucleus pulposus progenitor cells with ageing and degeneration of the intervertebral disc; 2012 – newly cited – herein referred to as “Sakai 2012”), as evidenced by Dantherm (Harnessing heat for effective disinfection; 2025 – previously cited).
Masuda’s general disclosure relates to promoting the synthesis of collagen and proteoglycan in chondrocytes, such as intervertebral disc cells, articular chondrocytes, and meniscal cells, through administration of an extract from inflamed tissue inoculated with vaccinia virus (see, e.g., Masuda, abstract). Moreover, Masuda discloses that “a preparation of an extract from inflamed skins of rabbits inoculated with vaccinia virus is commercially available as a pharmaceutical product” and that “the preparation is known to be effective against low back pain, cervicobrachial syndrome, symptomatic neuralgia, periarthritis scapulohumeralis, osteoarthritis, itchiness accompanied with skin diseases (eczema, dermatitis, urticaria), allergic rhinitis, sequelae of subacute myelo-optico-neuropathy such as coldness, paresthesia and pain, postherpetic neuralgia and the like” (see, e.g., Masuda, [0012]).
Regarding claims 1-4 pertaining to determining or evaluating an extract from inflamed tissues inoculated with vaccinia virus, Masuda teaches a method of contacting intervertebral disc cells with an extract from inflamed tissue inoculated with vaccinia virus, wherein the extract is administered to intervertebral disc cells (see, e.g., Masuda, [0030], Example 3). In Example 3, Masuda teaches that the extract is added to intervertebral disc cells in order to test the metabolism of proteoglycan and collagen synthesis (see, e.g., Masuda, [0030]). Prior to determining if the extract increases proteoglycan metabolism and collagen synthesis in Example 3, Masuda teaches that the extraction liquid is heated for deproteinization (see, e.g., Masuda, [0017]). Moreover, one of ordinary skill in the art would readily understand that heating the extract would also inherently result in disinfection because heat is used to kill pathogens (see, e.g., Dantherm, Evidence of the Record, Introduction). Furthermore, Masuda teaches “ the deproteinized solution is adjusted to an alkaline condition, heated, and then filtered or centrifuged” (see, e.g., Masuda, [0017]); therefore, heating the extract again after deproteinization would result in disinfection.
Regarding claim 5 pertaining to the inflamed tissues, Masuda teaches “a preparation of an extract from inflamed skins of rabbits inoculated with vaccinia virus is commercially available as a pharmaceutical product, and may be employed in the present invention” (see, e.g., Masuda, [0012]). Moreover, Masuda teaches that the preparation “is a medicinal agent containing non-proteinous active substances extracted and separated from the inflamed skin tissue of rabbits inoculated with vaccinia virus” (see, e.g., Masuda, [0012]).
Regarding claim 7 pertaining to the preparation, Masuda teaches that the preparation can be formed for intramuscular and intravenous injection, and as a tablet (see, e.g., Masuda, [0012]).
However, Masuda does not teach: measuring the expression of an N-acetylgalactosaminyltransferase (claim 1); or measuring expression of angiopoietin 1 (claim 1); or wherein the N-acetylgalactosaminyltransferase is at least one selected from the group consisting of N-acetylgalactosaminyltransferase-1 and N-acetylgalactosaminyltransferase 2 (claims 1-3); or comparing expression increase rates between N-acetylgalactosaminyltransferase 1 and N-acetylgalactosaminyltransferase 2 (claim 4).
Sakai’s general disclosure relates to demonstrating that chondroitin sulfate N-acetylgalactosaminyltransferase 1 plays a critical role in chondroitin sulfate biosynthesis in cartilage (see, e.g., Sakai, abstract). Moreover, Sakai discloses that chondroitin sulfate N-acetylgalactosaminyltransferase 1 exhibits the highest level of expression in developing cartilage (see, e.g., Sakai, abstract). Furthermore, Sakai identified that chondroitin sulfate N-acetylgalactosaminyltransferase 1 is critical for cartilage CS biosynthesis and overexpression of the enzyme leads to elevated levels of CS biosynthesis (see, e.g., Sakai, Introduction, pg. 4153).
Regarding claims 1-4 pertaining to measuring N-acetylgalactosaminyltransferase, Sakai teaches that N-acetylgalactosaminyltransferase 1 is critical for cartilage CS biosynthesis and has the highest level of expression in developing cartilage (see, e.g., Sakai, abstract & Introduction, pg. 4153). Moreover, Sakai teaches that upon measuring and comparing expression of N-acetylgalactosaminyltransferase 1 and N-acetylgalactosaminyltransferase 2 in developing mouse cartilage, chondroitin sulfate N-acetylgalactosaminyltransferase 1 is expressed at the highest level, while chondroitin sulfate N-acetylgalactosaminyltransferase 2 is expressed at very low levels (see, e.g., Sakai, Figure 2 & Results, pg. 4155).
Sakai 2012’s general disclosure relates to identification of “progenitor cells that are Tie2 positive (Tie2+) and disialoganglioside 2 positive (GD2+), in the nucleus pulposus from mice and humans. These cells form spheroid colonies that express type II collagen and aggrecan. They are clonally multipotent and differentiated into mesenchymal lineages and induced reorganization of nucleus pulposus tissue when transplanted into non-obese diabetic/severe combined immunodeficient mice. The frequency of Tie2+ cells in tissues from patients decreases markedly with age and degeneration of the intervertebral disc, suggesting exhaustion of their capacity for regeneration. However, progenitor cells (Tie2+GD2+) can be induced from their precursor cells (Tie2+GD2-) under simple culture conditions. Moreover, angiopoietin-1, a ligand of Tie2, is crucial for the survival of nucleus pulposus cells” (see, e.g., Sakai 2012, abstract).
Regarding claim 1 pertaining to measuring angiopoietin 1, Sakai 2012 teaches measuring angiopoietin 1 in nucleus pulposus cells by real time PCR (see, e.g., Sakai 2012, Supplementary Methods, pg. 17). Sakai 2012 teaches that intervertebral disc cells are composed of nucleus pulposus cells (see, e.g., Sakai 2012, Introduction, pg. 2); therefore, intervertebral disc cells inherently contain nucleus pulposus cells and angiopoietin 1 is being measured in these cells.
It would have been firstly obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to measure N-acetylgalactosaminyltransferase, such as N-acetylgalactosaminyltransferase 1 and N- N-acetylgalactosaminyltransferase 1, as taught by Sakai, in an assay wherein intervertebral disc cells are contacted with an extract derived from inflamed tissues inoculated with vaccinia virus, as taught by Masuda. One would have been motivated to do so because Sakai teaches that N-acetylgalactosaminyltransferase 1 is critical for cartilage CS biosynthesis and has the highest level of expression in developing cartilage (see, e.g., Sakai, abstract & Introduction, pg. 4153). Therefore, one of ordinary skill in the art would want to measure expression of N-acetylgalactosaminyltransferase in order to evaluate cartilage biosynthesis. Moreover, Masuda teaches an assay in Example 3, wherein the extract is added to chondrocytes in order to measure proteoglycan metabolism and collagen synthesis (see, e.g., Masuda, Example 3). From Example 3, Masuda teaches that the extract promotes the synthesis of collagen and proteoglycan in chondrocytes such as intervertebral disc cells, “it is indicated that NTP has a regenerating activity on a chondrocyte extracellular matrix of various cartilages (see, e.g., Masuda, [0041]). Therefore, based on the teachings of Masuda and Sakai, it would have been obvious to measure expression of chondroitin sulfate N-acetylgalactosaminyltransferase 1 because this enzyme is highly expressed in developing cartilage, wherein cartilage is present in intervertebral disc cells, and one would want to measure N-acetylgalactosaminyltransferase 1 to determine if the treatment is working based on cartilage biosynthesis. Additionally, one of ordinary skill in the art would want to use expression of N-acetylgalactosaminyltransferase as an index following neurotropin treatment in order to determine if the treatment did or did not work as it pertains to cartilage biosynthesis. One would have expected success because Masuda and Sakai both teach regeneration of extracellular matrix components, especially cartilage.
It would have been secondly obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to measure angiopoietin 1, as taught by Sakai 2012, in intervertebral disc cells following contact with an extract derived from inflamed tissues inoculated with vaccinia virus, as taught by Masuda. One would have been motivated to do so because angiopoietin 1 is important for maintaining progenitor cells and protecting nucleus pulposus cells from apoptosis, which correlates to intervertebral disc degeneration and ageing (see, e.g., Sakai 2012, Introduction, pg. 2). Furthermore, Sakai 2012 teaches that the signaling between Tie2 and angiopoietin 1 plays a role in nucleus pulposus cell maintenance and survival (see, e.g., Sakai 2012, Discussion, pg. 9); therefore, angiopoietin 1 is a marker in nucleus pulposus cells, which are inherently contained in intervertebral disc cells, for cellular survival and regeneration and/or maintenance of progenitor cells. Therefore, one of ordinary skill in the art would want to measure expression of angiopoietin 1 in order to evaluate intervertebral disc cell regeneration. Moreover, Masuda teaches in Example 3 an assay wherein the extract is added to chondrocytes to measure proteoglycan metabolism and collagen synthesis, and it was determined that the extract promotes the synthesis of collagen and proteoglycan in chondrocytes such as intervertebral disc cells, “it is indicated that NTP has a regenerating activity on a chondrocyte extracellular matrix of various cartilages (see, e.g., Masuda, [0041]). Therefore, based on the teachings of Masuda and Sakai 2012, it would have been obvious to measure angiopoietin 1 after contacting intervertebral disc cells with an extract derived from inflamed tissues inoculated with vaccinia virus in order to look at measure regeneration of the cells since the extract contains regeneration capabilities and angiopoietin 1 is a marker for regeneration. Additionally, one would want to measure angiopoietin 1 to determine if the treatment is working based on intervertebral disc cell regeneration. Additionally, one of ordinary skill in the art would want to use expression of angiopoietin 1 as an index following neurotropin treatment in order to determine if the treatment did or did not work as it pertains to intervertebral disc cell regeneration. One would have expected success because Masuda and Sakai 2012 both teach regeneration of intervertebral disc cells.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Masuda, Sakai, Sakai 2012, and Dantherm as applied to claims 1-5 and 7 above, and further in view of Okuda (Mechanisms of Age-Related Decline in Insulin-Like Growth Factor-I Dependent Proteoglycan Synthesis in Rat Intervertebral Disc Cells; 2001 – newly cited).
The references of Masuda, Sakai, Sakai 2012, and Dantherm are discussed above.
Regarding claim 8, Masuda teaches a method of contacting intervertebral disc cells with an extract from inflamed tissue inoculated with vaccinia virus, wherein the extract is administered to intervertebral disc cells (see, e.g., Masuda, [0030], Example 3). In Example 3, Masuda teaches that the extract is added to intervertebral disc cells in order to test the metabolism of proteoglycan and collagen synthesis (see, e.g., Masuda, [0030]).
However, the references do not teach: measuring expression of insulin like growth factor 1 (IGF1) in the intervertebral disc cells (claim 8).
Okuda’s general disclosure relates to determining “whether synthetic responses to insulin-like growth factor-I decline with age and to explore the possibility that an age-related increase in the expression of insulin-like growth factor binding proteins suppresses matrix synthesis in intervertebral disc cells” (see, e.g., Okuda, abstract). Additionally, Okuda discloses “age related decline in insulin-like growth factor-I dependent proteoglycan synthesis in nucleus pulposus is caused, at least in part, by the increase in insulin-like growth factor binding proteins at the early stages of aging, and further suggest that a loss of proteoglycan synthesis during the late stages of aging is caused by the downregulation of insulin-like growth factor-I receptor in addition to an increase in insulin-like growth factor binding proteins” (see, e.g., Okuda, abstract).
Regarding claim 8 pertaining to measuring expression of IGF1, Okuda teaches that the concentration of IGF1 secreted by nucleus pulposus from intervertebral disc cells was measured by radio immunoassay using a Somatomedin-C Eiken II Kit, and the concentration of secreted IGF1 per 1x105 cultured cells was calculated (see, e.g., Okuda, Materials and Methods, pg. 2422).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to measure IGF1, as taught by Okuda, in intervertebral disc cells following contact with an extract derived from inflamed tissues inoculated with vaccinia virus, as taught by Masuda, Sakai, and Sakai 2012. One would have been motivated to do so because Okuda teaches IGF1 activates matrix metabolism, particularly proteoglycan synthesis, to induce proliferation of chondrocytes, which are contained within intervertebral disc cells (see, e.g., Okuda, Introduction, pg. 2421). Additionally, Okuda teaches that IGF1 is a regulator of proteoglycan synthesis in intervertebral disc cells, and the responsiveness of chondrocytes to IGF1 decreases with age and in osteoarthritis (see, e.g., Okuda, Introduction, pg. 2422). Okuda teaches that from their studies, it appears that that there is an age-related decline in IGF1-dependent proteoglycan synthesis in rat intervertebral discs (see, e.g., Okuda, Discussion, pg. 2425). Therefore, one of ordinary skill in the art would want to measure expression of IGF1 in order to evaluate proteoglycan biosynthesis and chondrocyte proliferation in intervertebral disc cells. Moreover, Masuda teaches in Example 3 an assay for treating chondrocytes with an extract derived from inflamed tissues inoculated with vaccinia virus, followed by measuring expression of collagen and proteoglycan metabolism following treatment, wherein treatment with the extract resulted in increased proteoglycan metabolism and collagen synthesis following treatment (see, e.g., Masuda, Example 3). Therefore, based on the prior art teachings, it would have been obvious to measure IGF1 in the intervertebral disc cells since IGF1 is associated with proteoglycan synthesis and the extract derived from tissues of rabbits inoculated with vaccinia virus promotes synthesis of proteoglycan in intervertebral disc cells. Additionally, one would want to measure IGF1 in intervertebral disc cells to determine if the treatment is working based proteoglycan biosynthesis and chondrocyte proliferation in intervertebral disc cells. Additionally, one of ordinary skill in the art would use expression of IGF1 as an index following neurotropin treatment in order to determine if the treatment did or did not work as it pertains to proteoglycan biosynthesis and chondrocyte proliferation in intervertebral disc cells. One would have expected success because Masuda, Sakai, Sakai 2012, and Okuda teach synthesis of proteoglycan and/or cartilage in intervertebral disc cells.
Claims 9-14 are rejected under 35 U.S.C. 103 as being unpatentable over Masuda (US 2013/0164383; Date of Publication: June 27, 2013 – previously cited) in view of Sakai (Chondroitin Sulfate N-Acetylgalactosaminyltransferase-1 Plays a Critical Role in Chondroitin Sulfate Synthesis in Cartilage; 2006 – cited in the IDS filed on 12/30/2024 & previously cited), and Okuda (Mechanisms of Age-Related Decline in Insulin-Like Growth Factor-I Dependent Proteoglycan Synthesis in Rat Intervertebral Disc Cells; 2001 – newly cited), and evidenced by Dantherm (Harnessing heat for effective disinfection; 2025 – previously cited).
Masuda’s general disclosure is discussed above.
Regarding claims 9-12 pertaining to determining or evaluating an extract from inflamed tissues inoculated with vaccinia virus, Masuda teaches a method of contacting intervertebral disc cells with an extract from inflamed tissue inoculated with vaccinia virus, wherein the extract is administered to intervertebral disc cells (see, e.g., Masuda, [0030], Example 3). In Example 3, Masuda teaches that the extract is added to intervertebral disc cells in order to test the metabolism of proteoglycan and collagen synthesis (see, e.g., Masuda, [0030]). Prior to determining if the extract increases proteoglycan metabolism and collagen synthesis in Example 3, Masuda teaches that the extraction liquid is heated for deproteinization (see, e.g., Masuda, [0017]). Moreover, one of ordinary skill in the art would readily understand that heating the extract would also inherently result in disinfection because heat is used to kill pathogens (see, e.g., Dantherm, Evidence of the Record, Introduction). Furthermore, Masuda teaches “ the deproteinized solution is adjusted to an alkaline condition, heated, and then filtered or centrifuged” (see, e.g., Masuda, [0017]); therefore, heating the extract again after deproteinization would result in disinfection.
Regarding claim 13 pertaining to the inflamed tissues, Masuda teaches “a preparation of an extract from inflamed skins of rabbits inoculated with vaccinia virus is commercially available as a pharmaceutical product, and may be employed in the present invention” (see, e.g., Masuda, [0012]). Moreover, Masuda teaches that the preparation “is a medicinal agent containing non-proteinous active substances extracted and separated from the inflamed skin tissue of rabbits inoculated with vaccinia virus” (see, e.g., Masuda, [0012]).
Regarding claim 14 pertaining to the preparation, Masuda teaches that the preparation can be formed for intramuscular and intravenous injection, and as a tablet (see, e.g., Masuda, [0012]).
However, Masuda does not teach: measuring the expression of an N-acetylgalactosaminyltransferase (claim 9); or measuring expression of IGF1 (claim 9); or wherein the N-acetylgalactosaminyltransferase is at least one selected from the group consisting of N-acetylgalactosaminyltransferase-1 and N-acetylgalactosaminyltransferase 2 (claims 9-11); or comparing expression increase rates between N-acetylgalactosaminyltransferase 1 and N-acetylgalactosaminyltransferase 2 (claim 12).
Sakai’s general disclosure relates to demonstrating that chondroitin sulfate N-acetylgalactosaminyltransferase 1 plays a critical role in chondroitin sulfate biosynthesis in cartilage (see, e.g., Sakai, abstract). Moreover, Sakai discloses that chondroitin sulfate N-acetylgalactosaminyltransferase 1 exhibits the highest level of expression in developing cartilage (see, e.g., Sakai, abstract). Furthermore, Sakai identified that chondroitin sulfate N-acetylgalactosaminyltransferase 1 is critical for cartilage CS biosynthesis and overexpression of the enzyme leads to elevated levels of CS biosynthesis (see, e.g., Sakai, Introduction, pg. 4153).
Regarding claims 9-12 pertaining to measuring N-acetylgalactosaminyltransferase, Sakai teaches that N-acetylgalactosaminyltransferase 1 is critical for cartilage CS biosynthesis and has the highest level of expression in developing cartilage (see, e.g., Sakai, abstract & Introduction, pg. 4153). Moreover, Sakai teaches that upon measuring N-acetylgalactosaminyltransferase 1 and N-acetylgalactosaminyltransferase 2 in developing mouse cartilage, chondroitin sulfate N-acetylgalactosaminyltransferase 1 is expressed at the highest level, while chondroitin sulfate N-acetylgalactosaminyltransferase 2 is expressed at very low levels (see, e.g., Sakai, Figure 2 & Results, pg. 4155).
Okuda’s general disclosure relates to determining “whether synthetic responses to insulin-like growth factor-I decline with age and to explore the possibility that an age-related increase in the expression of insulin-like growth factor binding proteins suppresses matrix synthesis in intervertebral disc cells” (see, e.g., Okuda, abstract). Additionally, Okuda discloses “age related decline in insulin-like growth factor-I dependent proteoglycan synthesis in nucleus pulposus is caused, at least in part, by the increase in insulin-like growth factor binding proteins at the early stages of aging, and further suggest that a loss of proteoglycan synthesis during the late stages of aging is caused by the downregulation of insulin-like growth factor-I receptor in addition to an increase in insulin-like growth factor binding proteins” (see, e.g., Okuda, abstract).
Regarding claim 9 pertaining to measuring expression of IGF1, Okuda teaches that the concentration of IGF1 secreted by nucleus pulposus from intervertebral disc cells was measured by radio immunoassay using a Somatomedin-C Eiken II Kit, and the concentration of secreted IGF1 per 1x105 cultured cells was calculated (see, e.g., Okuda, Materials and Methods, pg. 2422).
It would have been first obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to measure N-acetylgalactosaminyltransferase, such as N-acetylgalactosaminyltransferase 1 and N-acetylgalactosaminyltransferase 1, as taught by Sakai, in intervertebral disc cells following contact with an extract derived from inflamed tissues inoculated with vaccinia virus, as taught by Masuda. One would have been motivated to do so because Sakai teaches that N-acetylgalactosaminyltransferase 1 is critical for cartilage CS biosynthesis and has the highest level of expression in developing cartilage (see, e.g., Sakai, abstract & Introduction, pg. 4153). Therefore, one of ordinary skill in the art would want to measure expression of N-acetylgalactosaminyltransferase in order to evaluate cartilage biosynthesis in intervertebral disc cells. Moreover, Masuda teaches that since neurotropin (i.e., NTP; “a nonprotein extract from the inflamed skin of rabbits following inoculation with vaccinia virus as an active ingredient” (see, e.g., Masuda, [0002])) promotes the synthesis of collagen and proteoglycan in chondrocytes such as intervertebral disc cells, “it is indicated that NTP has a regenerating activity on a chondrocyte extracellular matrix of various cartilages (see, e.g., Masuda, [0041]). Therefore, based on the teachings of Masuda and Sakai, it would have been obvious to measure expression of chondroitin sulfate N-acetylgalactosaminyltransferase 1 because this enzyme is highly expressed in developing cartilage, wherein cartilage is present in intervertebral disc cells, and one would want to measure N-acetylgalactosaminyltransferase 1 to determine if the treatment is working based on cartilage biosynthesis. Additionally, one of ordinary skill in the art would want to use expression of N-acetylgalactosaminyltransferase as an index in order to determine if the neurotropin treatment did or did not work as it pertains to cartilage biosynthesis. One would have expected success because Masuda and Sakai both teach regeneration of extracellular matrix components, especially cartilage.
It would have been secondly obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to measure IGF1, as taught by Okuda, in intervertebral disc cells following contact with an extract derived from inflamed tissues inoculated with vaccinia virus, as taught by Masuda. One would have been motivated to do so because Okuda teaches IGF1 activates matrix metabolism, particularly proteoglycan synthesis, to induce proliferation of chondrocytes, which are contained within intervertebral disc cells (see, e.g., Okuda, Introduction, pg. 2421). Additionally, Okuda teaches that IGF1 is a regulator of proteoglycan synthesis in intervertebral disc cells, and the responsiveness of chondrocytes to IGF1 decreases with age and in osteoarthritis (see, e.g., Okuda, Introduction, pg. 2422). Okuda teaches that from their studies, it appears that there is an age-related decline in IGF1-dependent proteoglycan synthesis in rat intervertebral discs (see, e.g., Okuda, Discussion, pg. 2425). Therefore, one of ordinary skill in the art would want to measure expression of IGF1 in order to evaluate proteoglycan biosynthesis and chondrocyte proliferation in intervertebral disc cells. Moreover, Masuda teaches that since neurotropin (i.e., NTP; “a nonprotein extract from the inflamed skin of rabbits following inoculation with vaccinia virus as an active ingredient” (see, e.g., Masuda, [0002])) promotes the synthesis of collagen and proteoglycan in chondrocytes such as intervertebral disc cells, “it is indicated that NTP has a regenerating activity on a chondrocyte extracellular matrix of various cartilages (see, e.g., Masuda, [0041]). Therefore, based on the teachings of Masuda and Okuda, it would have been obvious to measure IGF1 in the intervertebral disc cells since IGF1 is associated with proteoglycan synthesis and the extract derived from tissues of rabbits inoculated with vaccinia virus promotes synthesis of proteoglycan in intervertebral disc cells. Additionally, one would want to measure IGF1 in intervertebral disc cells to determine if the treatment is working based proteoglycan biosynthesis and chondrocyte proliferation in intervertebral disc cells. Additionally, one of ordinary skill in the art would use expression of IGF1 as an index following neurotropin treatment in order to determine if the treatment did or did not work. One would have expected success because Masuda and Okuda both teach synthesis of proteoglycan in intervertebral disc cells.
Examiner’s Response to Arguments
Regarding Applicant’s arguments that the cited references do not teach amended claims 1 and 9 as it pertains to measuring expression levels of angiopoietin 1 and insulin like growth factor 1 (remarks, pages 5-7), as stated above, all previous rejections under 35 U.S.C. 103 have been withdrawn; however, new grounds of rejection are set forth above. Although Masuda and Sakai were relied upon in the above presented rejections, they were not relied upon to teach the new limitations pertaining to measuring expression levels of angiopoietin 1 and insulin like growth factor 1. Therefore, Applicant’s argument are moot.
Conclusion
Claims 1-5 and 7-14 are rejected.
No claims are allowed.
Correspondence Information
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/NATALIE IANNUZO/Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653
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