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
This application is a CONTINUATION of U.S. Patent Application No. 17/274,404, filed 03/05/2025. Acknowledgement is made of the applicant’s claim for benefit to prior-filed U.S. patent applications 17/274,404 (filed 03/08/2021), PCT Application PCT/CA2019/051343 (filed 09/20/2019) and U.S. Provisional Application 62/734,127 (filed 09/20/2018).
Election/Restrictions
Applicant's election with traverse of group I, claims 1-16, drawn to an in vitro method of inducing differentiation of stem cells, in the reply filed on 07/01/2026 is acknowledged. The traversal is on the ground(s) that the restriction between group I and group II needs to be withdrawn since the colostrum derived mesenchymal stem cells of group II have a unique marker profile, therefore the method of Group I performed on bone marrow mesenchymal stem cells would not be expected to produce the same population of differentiated neural cells as defined in group II (Remarks, p2-3).
This is not found persuasive because MPEP 806.05(f) states: “[a] process of making and a product made by the process can be shown to be distinct inventions if either or both of the following can be shown: (A) that the process as claimed is not an obvious process of making the product and the process as claimed can be used to make another materially different product; or (B) that the product as claimed can be made by another materially different process”. In instant case, group I is directed to a process of making neural cells, and group II is directed to neural cells being made. The claims do not define the neural cells are specific neural cells which i.e., have specific cell markers, therefore the neural cells can be made/differentiated by other stem cells such as bone marrow mesenchymal stem cells. Thus group I and group II are distinct.
The requirement is still deemed proper and is therefore made FINAL. Accordingly, claims 1-16 have been considered on the merits. Claims 17-25 are withdrawn from consideration pursuant 37 CFR 1.142(b).
Claim Objections
Claim 7 is objected to because of the following informalities: claim 7 recites “…is included in the an amount of 2-30% or 8-20%” in lines 3-4. The word “the” before the word “an” needs to be deleted. 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.
Claims 7, 15 and 16 are 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 7, the claim recites “wherein the casein depleted fraction of whey derived from colostrum includes less than 20%, or less than 10%, or less than 2% on a wt/vol basis of the casein, or wherein the casein depleted fraction of whey derived from colostrum is included in an amount of 2-30% or 8-20%, on a vol/vol basis”. The claim is vague and confusing. The recitation ” wherein the casein depleted fraction of whey derived from colostrum includes less than 20%, or less than 10%, or less than 2% on a wt/vol basis of the casein” appears to limit the amount of casein in the casein depleted fraction of whey derived from colostrum, while the recitation “wherein the casein depleted fraction of whey derived from colostrum is included in an amount of 2-30% or 8-20%, on a vol/vol basis” uses the passive voice making it unclear whether the limitation means the volume percentage of casein in the casein depleted fraction of whey derived from colostrum, or the volume percentage of the casein depleted fraction of whey derived from colostrum in the serum-free mammalian cell culture medium. Therefore the scope of the claim is indefinite.
Regarding claim 15, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 16, the phrase "for example" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim Interpretation
As stated above, claim 7 is indefinite. In the interest of compact prosecution, in claim 7, the recitation “wherein the casein depleted fraction of whey derived from colostrum is included in the an amount of 2-30% or 8-20%, on a vol/vol basis” is interpreted as the volume percentage of the casein depleted fraction of whey derived from colostrum in the serum-free mammalian cell culture medium is 2-30% or 8-20%, on a vol/vol basis.
Similarly, claims 15 and 16 are interpreted that the limitations following the phrases “such as“ and “for example” as not required for the claimed invention.
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.
Claims 1-4, 7-14 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Hosseini et al. (Neurol Res Int. 2014;2014:807896, cited in IDS) in view of Cregan et al. (US 7,776,586 B2, cited in IDS) and Aalto et al. (93/08264, published in 1993), as evidenced by Ottenhof (US 4,519,945, patented in 1985).
Hosseini et al. teach differentiating the breast milk-derived stem cells (BMDSC) toward neural stem cells and then into the neurons and neuroglia (Abstract).
Regarding claim 1, Hosseini et al. teach differentiating the breast milk-derived stem cells (BMDSC) toward neural stem cells and then into the neurons and neuroglia. The breast milk-derived stem cells (BMDSC) were isolated from human breast milk and cultured in Dulbecco’s modified Eagle medium/F12 (DMEM/F12) containing fibroblast growth factor (bFGF) (see Abstract). This teaching reads on “an in vitro method of inducing differentiation of stem cells, comprising: obtaining a population of breast milk-derived stem cells; and culturing the breast milk-derived stem cells in a mammalian cell culture medium, to produce a population of differentiated neural cells”.
Hosseini et al. do not teach: (1) using colostrum derived stem cells for the culture; (2) the culture medium is supplemented with a casein depleted fraction of whey derived from colostrum. However, such was disclosed by Cregan et al. and Aalto et al. at the time of instant invention.
Cregan et al. teach a method for isolating progenitor cells from a human body, inclusive of all cells with stem cell-like characteristics, in particular pluripotent or multi potent progenitor cells, wherein such cells are directly or indirectly derived from human mammary secretion, be it colostrum, mature milk, or dry period secretion from males or females, of said human body during at least one of the following periods: non-pregnant period, pregnant period, lactating period, involuting period (Abstract).
Aalto et al. teach a process for preparing said colostrum fraction (p6, L28-29), as well as a process for preparing said colostrum fraction (p6, L32-34).
Regarding limitation (1) using colostrum derived stem cells for the culture, Cregan et al. teach cells with stem cell-like characteristics, in particular pluripotent or multi potent progenitor cells, can be directly or indirectly derived from human mammary secretion, including colostrum and mature milk (see Abstract).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Hosseini et al.’s method of differentiating the breast milk-derived stem cells (BMDSC) toward neural stem cells, and use colostrum derived stem cells for the culture based on Cregan et al.’s teaching. The only difference between instant claim and Hosseini et al.’s method of differentiating the breast milk-derived stem cells (BMDSC) toward neural stem cells is instant claim uses colostrum derived stem cells for the culture. Given that Cregan et al. teach both colostrum and mature milk have cells with stem cell-like characteristics, in particular pluripotent or multi potent progenitor cells (see Abstract), one of ordinary skill in the art would have substituted Hosseini et al.’s breast milk-derived stem cells (BMDSC) for colostrum derived stem cells according to their research interest. This simple substitution of one known element (differentiating the colostrum derived stem cells toward neural stem cells) for another known element (differentiating the BMDSC toward neural stem cells) is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, B.).
Regarding (2) using a casein depleted fraction of whey derived from colostrum as a supplement of culture medium, Aalto et al. teach a fraction having a very low protein and immunoglobulin
concentration and a negligible endotoxin concentration can be prepared from bovine colostrum. The final product contains all growth factors, trace elements, vitamins and other small-molecular compounds essential for cell proliferation present in colostrum (p8, L7-13). Aalto et al. also teach the method of obtaining the casein depleted fraction of whey derived from colostrum: casein can be removed by acid precipitation by decreasing the pH of the mixture (p10, L2-3). After the separation of the precipitate, the mixture is neutralized and the obtained precipitate is removed. Colostrum whey can thus be obtained (p10, L11-13).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Hosseini et al.’s method of differentiating the breast milk-derived stem cells (BMDSC) toward neural stem cells, and add a casein depleted fraction of whey derived from colostrum as a supplement of culture medium as taught by Aalto et al.. The skilled artisan would have been motivated to add a casein depleted fraction of whey derived from colostrum as a supplement of culture medium since Aalto et al. teach casein depleted fraction of whey derived from colostrum has growth-promoting activity, wherein this fraction has a low concentration of protein, endotoxin and immunoglobulin (see i.e., p8, L7-13). There would be a reasonable expectation of success of adding a casein depleted fraction of whey derived from colostrum as a supplement of culture medium, since Aalto et al. teach the method of preparing such fraction from colostrum (see, i.e., Examples 1 and 2).
Regarding claim 2, following the discussion above, Hosseini et al. teach differentiating BMDSC into neural stem cells: isolated cells were cultured in gelatin coated plates with concentration of
10000 cells/cm2 with DMEM/F12, 1% B27, and 2% N2 (p2, right column), which is a serum-free medium. In addition, Aalto et al. teach i.e., Example 5, the function of the fraction was tested with three different cell types. To obtain subcultures, the cells were washed once with PBS and suspended in a base medium supplemented with varying amounts (0 to 20%) of ultrafiltrate and 5 mg/ml transferrin (p19, L17-21). The result shows the ultrafiltrate promotes the growth of all cell lines, although the different cell types react in different ways (p20, L17-20). This teaching reads on the mammalian cell culture medium is serum-free and is supplemented with the casein depleted fraction of whey before the cultured cells become adherent and proliferate in the serum-free mammalian cell culture medium.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Hosseini et al.’s method of differentiating the breast milk-derived stem cells (BMDSC) toward neural stem cells, and add a casein depleted fraction of whey derived from colostrum as a supplement of culture medium before the cells become adherent and proliferate in the culture medium as taught by Aalto et al.. The skilled artisan would have been motivated to add a casein depleted fraction of whey derived from colostrum as a supplement of culture medium since Aalto et al. teach casein depleted fraction of whey derived from colostrum has growth-promoting activity, wherein this fraction has a low concentration of protein, endotoxin and immunoglobulin (see i.e., p8, L7-13). There would be a reasonable expectation of success of adding a casein depleted fraction of whey derived from colostrum in culture medium before the cells become adherent and proliferate, since Aalto et al. teach the method of preparing such fraction from colostrum (see, i.e., Examples 1 and 2) and the method of adding the a casein depleted fraction of whey derived from colostrum for culturing cells (see i.e., Example 5).
Regarding claim 3, Hosseini et al. teach differentiation of BMDSC into neural stem cell (p2, right column). The isolated BMDSC cells were cultured in gelatin coated plates with concentration of 10000 cells/cm2 with DMEM/F12, 1% B27, and 2% N2 for 7–10 days. The 7-10 days reads on “at least 48 hours” as recited in instant claim.
Regarding claim 4, following the discussion above, Hosseini et al. teach the differentiated cells were cultured in appropriate media (DMEM/F12 containing B27, N2, bFGF 10 𝜇g/mL, and EGF 20 𝜇g/mL, NS-A media). The media were removed every 3–5 days and changed with the fresh ones. The cells were incubated in 5% CO2 at 37°C for 7 days. Then, the spheres were formed and each cell of these spheres was capable of providing another sphere by passaging (p2, right column-p3, left column). This teaching indicates the stem cells can be proliferated by culturing for more than 7 days, i.e., 14 days by passaging. Moreover, it is not inventive to find optimal workable ranges (i.e., culturing period) by routine experimentation. See Jn re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Furthermore, Aalto et al. teach ultrafiltrate (a casein depleted fraction of whey derived from colostrum) promotes the growth of mammalian cells (see Example 5).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Hosseini et al.’s method of differentiating the breast milk-derived stem cells (BMDSC) toward neural stem cells, and add a casein depleted fraction of whey derived from colostrum as a supplement of culture medium as taught by Aalto et al. when proliferating the differentiated neural cells. The skilled artisan would have been motivated to add a casein depleted fraction of whey derived from colostrum as a supplement of culture medium when proliferating the differentiated neural cells since Aalto et al. teach casein depleted fraction of whey derived from colostrum has growth-promoting activity and promotes the growth of mammalian cells (see, i.e., Example 5). There would be a reasonable expectation of success of adding a casein depleted fraction of whey derived from colostrum in culture medium during proliferating the differentiated neural cells, since Aalto et al. teach the method of preparing such fraction from colostrum (see, i.e., Examples 1 and 2) and the method of adding the a casein depleted fraction of whey derived from colostrum for culturing cells (see i.e., Example 5).
Regarding claim 7, Aalto et al. teach for use as an additive in cell culture media, the colostrum fraction is added to a culture medium. The optimum concentration of the fraction is approximately 5 to 15%, although smaller amounts can also be used (p10, L27-29). The range of 5-15% is in the range of 2-30% as recited in instant claim.
Regarding claim 8, Hosseini et al. teach the culture of the isolated cells from the breast milk, the cells are cultured with the ES medium (DMEM/F12, KOSR (knockout serum replacement) 10%,
nonessential amino acid 1%, bFGF 10 𝜇g/mL, and pen/strep 1%) (p2, right column).
Regarding claim 9, Hosseini et al. teach figure 5 (see p5), neurons and astrocytes differentiated from breast milk stem cells-derived neural stem cell.
Regarding claim 10, following the discussion above, Hosseini et al. teach isolation of cells from milk: PBS was used to dilute the breast milk and they were centrifuged. Then, skim milk liquid component and fat layer were taken out. After washing using PBS, the cell pellet was resuspended in 10% fetal bovine serum within PBS (p2, right column, part 2.2). Then the isolated cells were cultured in plates coated with gelatin (p2, right column, part 2.3), then colony (adherent stem cells) were obtained.
Regarding claim 11, following the discussion above, Hosseini et al. teach culture of the isolated cells (p2, right column, part 2.3). Breast milk cells were cultured in plates coated with gelatin. After 5 days of culturing, each colony was separately selected and relocated in new dishes and cultured in medium in order to make feeder culture of the second and third ones. This teaching reads on the adherent stem cells are passaged for three or more passages prior to differentiation into neural stem cells. Moreover, it is not inventive to find optimal workable ranges (i.e., passages of cell culture to obtain enough stem cells) by routine experimentation. See Jn re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Regarding claim 12, following the discussion above, Aalto et al. teach Example 1, casein was precipitated at 56°C by adjusting the pH to 4.6 with addition of 2 M HCl. The mixture was stirred for 1 hour. The precipitate was then removed by centrifugation at 4°C and 10,000 g for 60 minutes. The clarified whey was filtered in succession by 0.8 μm and 0.22 μm filters (see p11-12, Example 1). It was an inherent property that precipitated casein produce/form curd, as evidenced by Ottenhof. Ottenhof teaches process for the preparation of a precipitate of casein and whey protein from a milk product (Abstract). Ottenhof teaches by this acidification a precipitate (also mentioned curd) is obtained (Col 3, L45-46). Therefore Aalto et al.’s teaching reads on the casein depleted fraction of whey is prepared by precipitating casein from a whey fraction of colostrum to produce curds, and then removing the curds by centrifugation and filtration to produce the casein depleted fraction of whey, as recited in instant claim.
Regarding claim 13, Aalto et al. teach casein can be removed by acid precipitation while decreasing the pH of the mixture (p10, L2-3).
Regarding claim 14, following the discussion above, Aalto et al. teach preparation of a fraction from bovine colostrum (see Examples 1 and 2), and Cregan et al. teach the colostrum derived stem cells are derived from human (see Abstract).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Hosseini et al.’s method of differentiating the breast milk-derived stem cells (BMDSC) toward neural stem cells, and add a casein depleted fraction of whey derived from bovine colostrum as a supplement of culture medium which is obtained by precipitating casein from a whey fraction using an acid as taught by Aalto et al.. The skilled artisan would have been motivated to add a casein depleted fraction of whey derived from colostrum as a supplement of culture medium since Aalto et al. teach casein depleted fraction of whey derived from colostrum has growth-promoting activity and promotes the growth of mammalian cells (see, i.e., Example 5). There would be a reasonable expectation of success of precipitating casein from a whey fraction using an acid, since Aalto et al. teach the method of precipitating (see, i.e., p10, L2-3).
Regarding claim 16, following the discussion above, Cregan et al. teach a method for isolating progenitor cells from a human body, inclusive of all cells with stem cell-like characteristics, in particular pluripotent or multipotent progenitor cells, wherein such cells are directly or indirectly derived from human mammary secretion, be it colostrum or mature milk (see Abstract). Cregan et al. also teach the subsequent use of these stem cells, or cells differentiated or dedifferentiated could include storage of these stem cells for future use as outlined below. This includes their storage for use in scientific research, clinical, diagnostic or commercial applications (Col 9, L40-45). This teaching reads on the colostrum derived stem cells are isolated and then preserved/stored, as recited in instant claim.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Hosseini et al.’s method of differentiating the breast milk-derived stem cells (BMDSC) toward neural stem cells, and use colostrum-derived stem cells in the method and isolate and then preserve (extra) colostrum-derived stem cells as taught by Cregan et al.. The skilled artisan would have been motivated to isolate and then preserve (extra) colostrum-derived stem cells since Cregan et al. teach multiple usages of colostrum and mature milk derived stem cells (see, i.e., Col 9-10). There would be a reasonable expectation of success of isolating and preserving colostrum-derived stem cells since Cregan et al. teach the method of isolation of colostrum-derived stem cells (see, i.e., Col7, “Cell isolation” part, as well as Col 8, alternative way of isolation, L11-14), and the method of preservation of stem cells are routine operation in the art.
Claims 1-14 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Hosseini et al. (Neurol Res Int. 2014;2014:807896, cited in IDS) in view of Cregan et al. (US 7,776,586 B2, cited in IDS) and Aalto et al. (WO 93/08264, published in 1993), as evidenced by Ottenhof (US 4,519,945, patented in 1985), further in view of Godhia et al. (Curr Res Nutr Food Sci 2013;1(1):37-47).
The teaching of Hosseini et al., Cregan et al. and Aalto et al. is set forth above.
Regarding claims 5 and 6, Hosseini et al., Cregan et al. and Aalto et al. do not specifically teach using colostrum derived stem cells are derived from colostrum collected from a mammal within 2-4 days of birth, or within 24 hours of birth, as well as the casein depleted fraction of whey is derived from colostrum collected from a mammal within 24 hours of birth. However, such was disclosed by Godhia et al. at the time of instant application.
Godhia et al. review the current knowledge on the beneficial effect of colostrum supplementation (Abstract).
Regarding claims 5 and 6, Godhia et al. teach colostrum is also called “foremilk”. It lasts for 2- 4
days after the lactation is started (p37, left column). The colostrum collected within 24 hours
contains maximum substances but less in amounts (p38, right column).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Hosseini et al. in view of Cregan et al. and Aalto et al.’s method of differentiating colostrum derived stem cells toward neural stem cells in a mammalian cell culture medium supplemented with a casein depleted fraction of whey derived from colostrum, and use the colostrum derived stem cells are derived from colostrum collected from a mammal within 2-4 days of birth or within 24 hours of birth, and/or use the casein depleted fraction of whey is derived from colostrum collected from a mammal within 24 hours of birth, as taught by Godhia et al.. The only difference between instant claim and Hosseini et al. in view of Cregan et al. and Aalto et al.’s method of differentiating colostrum derived stem cells toward neural stem cells in a mammalian cell culture medium supplemented with a casein depleted fraction of whey derived from colostrum is instant claims use colostrum from i.e., from a mammal within 24 hours of birth. Given that Godhia et al. teach colostrum lasts for 2- 4 days after the lactation is started, and colostrum collected within 24 hours
contains maximum substances but less in amounts, one of ordinary skill in the art would have substituted Cregan et al.’s colostrum for colostrum obtained from the time period of within 24 hours of birth according to their preference. This simple substitution of one known element (using colostrum of within 24 hours of birth) for another known element (colostrum in Cregan et al.’s teaching) is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, B.).
Allowable Subject Matter
Claim 15 is found free of art. However, claim 15 is dependent upon a rejected base claim, and is rejected as being indefinite. The claim would be allowable if overcome the 112(b) rejection, and rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
No claims are allowed.
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/Q.G./Examiner, Art Unit 1633
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699
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